WO2007121288A2 - Drug depot implant designs and methods of implantation - Google Patents

Drug depot implant designs and methods of implantation Download PDF

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Publication number
WO2007121288A2
WO2007121288A2 PCT/US2007/066496 US2007066496W WO2007121288A2 WO 2007121288 A2 WO2007121288 A2 WO 2007121288A2 US 2007066496 W US2007066496 W US 2007066496W WO 2007121288 A2 WO2007121288 A2 WO 2007121288A2
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WO
WIPO (PCT)
Prior art keywords
therapeutic agent
implant
drug depot
depot implant
tissue
Prior art date
Application number
PCT/US2007/066496
Other languages
French (fr)
Other versions
WO2007121288A3 (en
Inventor
William F. Mckay
Original Assignee
Warsaw Orthopedic, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Warsaw Orthopedic, Inc. filed Critical Warsaw Orthopedic, Inc.
Priority to JP2009505619A priority Critical patent/JP5081228B2/en
Priority to EP07760538A priority patent/EP2007353A2/en
Priority to CN2007800173992A priority patent/CN101442983B/en
Publication of WO2007121288A2 publication Critical patent/WO2007121288A2/en
Publication of WO2007121288A3 publication Critical patent/WO2007121288A3/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0085—Brain, e.g. brain implants; Spinal cord
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0097—Micromachined devices; Microelectromechanical systems [MEMS]; Devices obtained by lithographic treatment of silicon; Devices comprising chips
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • compositions include novel drug depot implant designs for optimal delivery of antiinflammatory agents and/or grow th factors to inhibit or eliminate the inflammatory response that may result in acute or chronic pain and further tissue damage after disease or injury
  • TNF- ⁇ tumor necrosis factor alpha
  • TNF- ⁇ inhibition is a target for pain therapy.
  • Pro- TNF- ⁇ is expressed on the plasma membrane, then cleaved in the extracellular domain
  • TNF- ⁇ acts through two receptors (TNFRs)' Type I receptors (p ⁇ O, p55, CO 120a) are expressed constitutive! y on most cell types and Type II receptors (p80, p75, CD 120b) are inducible.
  • Popular TNF- ⁇ inhibitors act primarily to inhibit binding of TNF-u to its receptors.
  • TNF inhibitors 1 monoclonal antibodies to TNF- ⁇ . which prevent binding of TNF- ⁇ to its two cell-associated signaling receptors (p55 and ⁇ 75) and 2) monomelic soluble forms of p55 or p75 TNFR dimerized by linking them to an immunoglobulin (Ig) Fc fragment. These lgs bind to TNF- ⁇ with high affinity and prevent it from binding to its cell -associated receptor.
  • TNF inhibitors have therefore been developed for therapeutic use for orthopedic and neuromuscular disease or injury that can cause pain, such as rheumatoid arthritis Cuiremly therapeutic agents are delivered systemically to treat bone- and caiu ' lage- related defects related to degeneration, injury, infection, malignancy or de ⁇ elopmenta!
  • alfoi ⁇ iatiou TNF inhibitors currently in use aie gcncially administered sjsteinically via intravenous infusion and subcutaneous injection, but there are side effects of anti-FNF therapies associated with the higher doses and systemic administration that are common with these therapies
  • a major disadvantage of these S ⁇ steim ' c drug delivery systems is thai the antiinflammatories are delivered in buffered solutions that have short half-lhes, therein requiring repeated administration to a patient, which can result in ad ⁇ erse effects due to the s ⁇ stem of deli ⁇ ery of relatk ely high doses of the drug Unfortunately, it provides a limited quantity of agent that must mo ⁇ e through the tissue to the target site
  • U S Patent Ko 6,203,813 discloses an opiate antagonist implant pellet for subcutaneous administration to a patient Aceoiding to the disclosure, the subcutaneous implant pellet releases the opiate antagonist in the patient to effectively inhibit the effects of a numb ⁇ of additive diugs to ueat dmg detoxification in a patient
  • the subcutaneous implant is not substantial!) immobilized in the tissue of a patient but is free to mo ⁇ e about under the skin
  • Anothei drawback to this approach is that the delivery of the therapeutic agent is accomplished via the general s ⁇ stemic circulatory s ⁇ stem, the therapeutic agent is not delKered locally to the affected area
  • U S Patent No 6,735,475 discloses small implantable stimulators W ⁇ h at least tuo electrodes that are small enough to hav e the electrodes located adjacent to a ner ⁇ e structure at least paitialiy responsible for headache and/or facial pain 1 he implant works ⁇ ia electrical stimulation of a specified tissue and does not include a theiapeutic agent component as part of the dev ice, let alone involve deliver ⁇ of a therapeutic agent to desired tissue
  • U S Patent No 6.735.475 describes a variety of implants for treating headache and/or facial pain, none of which arc suitable foi introducing therapeutic agents to a desired tissue of a patient.
  • 200400641*53 discloses an implant comprising collagen and/or other bioresorbable materials for deployment in select locations for regeneration of tissue According to the disclosure, the implant comprises a synthetic tissue substitute material and a method and system for deploying the implant.
  • U.S. Patent Application Publication No. 20040064193 describes a variety of implants for regeneration of tissue, none of which are suitable for introducing therapeutic agents to a desired tissue of a patient.
  • U S Patent Application Publication No. 20050074481 discloses an implantable device comprising a poly electrolytic complex for facilitating the healing of voids in bone, cartilage and soft tissue. According to the disclosure, the implant provides m vivo c ⁇ huring of tissue cells in a diverse tissue or homogeneous lesion
  • U S Patent Application Publication No. 20050074481 describes a variety of implants for facilitating the healing of voids in bone, cartilage and soft tissue, none of which are suitable for introducing therapeutic agents to a desired tissue of a patient.
  • 200501771 18 also discloses an implantable device comprising a polyelectrolytic complex for facilitating the healing of voids in bone, cartilage and soft tissue
  • the implant provides in vivo culturittg of tissue cells in a diverse tissue or homogeneous lesion, or for non- systemic delivery of one or more therapeutic agents to a patient.
  • the implant provides an electrical component as part of the device and does not include a therapeutic agent component as part of the device, let alone involve delivery of a therapeutic agent to desired tissue.
  • U.S. Patent Application Publication No 200501 52 C >49 discloses a method of intraarticular drug delivery comprising- selecting an attachment zone v ⁇ thin the subchondral bone in a synovial joint, affixing a drug release device in the attachment zone, the drug release device comprising a base affixabie in the attachment zone, a sustained release drug carrier and a drug, the device positioned so that the device releases the drug into the synovial fluid of the synovial joint and so thai agitation of the synovial fluid facilitates elution of the drug from the drug release de ⁇ ice
  • One drawback of these implants is that they are fixedly attached to the bone itself in a synovial joint
  • Another drawback of these implants is that many of the intended patients already suffer from pain and inflammation, and will be subjected to more pain upon implantation of the device into the bone and possible formation of osteophytes.
  • TNF inhibitors for the treatment and prevention of inflammation and pain, capable of being delivered for an extended period of time at, or in close proximity to, a 5 targeted site such as the site of trauma or inflammation.
  • the present invention fills the foregoing need by providing a drug depot implant comprising a physical structure to facilitate implantation and retention in a synovial joint, a disc space, a spinal canal, or a soft tissue surrounding the spinal canal of a subject; and a I 0 therapeutic agent that creates a concentration gradient for targeted delivers of the agent to the synovial joint, the disc space, the spinal canal, or the soft tissue surrounding the spinal canal, muscle, tendon, ligament, or cartilage of a subject.
  • One aspect of the present invention which provides the use of depots to deliver anti-inflammatory or anabolic compounds to intervertebral discs or articulating joints, has i 5 not been previously disclosed.
  • Another aspect of the present invention provides specific designs and methods for insertion of drug depots into discs or joint capsules with minimal tissue disruption and minimal interference with normal joint motion. The methods, systems and reagents of the present invention prevent the depots from migrating away from the inflamed tissue and allow for more uniform distribution of the drug.
  • One aspect of the invention provides a method for reducing pain and/or inflammation, which comprises administering to a target site in a subject in need of treatment an effective amount of a pharmaceutical composition comprising one or more therapeutic agents, wherein the one or more therapeutic agents are administered by a drug depot implant.
  • the drug depot implant comprises a body that holds 5 the therapeutic agent and an anchoring system that extends from the body to prevent migration of the body from the target site.
  • a solid depot wherein the therapeutic agent is in lyophilized form within the implant and slowly releases an effective therapeutic amount of agent into the desired location over a prolonged period of time, such 0 as for example, up to and including six months.
  • a drug depot implant is implanted in a subject at or near a target site
  • sites include an inflamed nerve, a synovial joint, or a spina! site, in particular a spinal disc site, such as the spinal disc space, the spinal canal or the surrounding soil tissue.
  • a drug depot iroplam design provides a physical feature to facilitate implantation and retention of the implant in the desired anatomical location for optimal clinical efficiency.
  • the drug depot design is a rod shaped implant loaded with a therapeutic agent.
  • One embodiment of the invention provides a rod shaped implant comprising small barbs that minimize migration of the implant in a patient's tissue once implanted
  • the present invention provides for methods, systems and reagents that permit a surgeon to deliver a drug depot implant with optimal efficiency to a target site in a subject in need of treatment
  • the implant is designed to limit '"backo ⁇ t" or forward movement into critical tissues
  • the implant is positioned in adjacent soft tissue to the spinal foramen space of inflamed nerve roots to alleviate sciatica and/or back pain caused by such inflammation
  • An alternative embodiment of the invention provides for a rod depot implant positioned into a disc space, wherein the implant is positioned in place by the barb.
  • the rod depot may further comprise a built-in cap or "stop" that positions the rod in place by utilizing an adjacent tissue plane, thereby permitting the active end of the rod to protrude into an aiea of inflamed tissue and elute the therapeutic agent, which may be, for example, an anti-inflammatory agent.
  • the drug depot implant is positioned in the knee joint, wherein the rod cap is positioned in place by the knee capsule and eiutes the therapeutic agent, such as an antiinflammatory agent, into the knee joint synovial fluid. Additional embodiments of the invention provide for positioning the drug depot implant in the shoulder, hip. other joints or spine of a patient
  • a targeted delivery system of one or more therapeutic agents is comenientlv a catheter.
  • the targeted delivery system is a syringe.
  • the targeted deliver)' system comprises a drag depot implant system administered locally by insertion of a catheter at or near a target site, the catheter having a proximal end and a distal end, the distal end having an opening to deliver a pharmaceutical in situ, the proximal end being fluidly connected to a pharmaceutical delivery pump
  • the proximal end of the catheter may deliver the therapeutic agent to within 10 cm of a target site, or more preferable, to within 5 cm of the target site, or even more preferable, to within 3 cm of the target site
  • the therapeutic agent could be delivered to the target site, adjacent to the target site, or from about 0 cm from the target site to about !0 cm from the target site, and may include every distance in-between.
  • the therapeutic agent may inhibit inflammation mediated by TNF- ⁇ , for example when the therapeutic agent is a TNF- ⁇ receptor inhibitor.
  • suitable therapeutic agents include, but are not limited to, soluble tumor necrosis factor ⁇ receptors, pegylated soluble tumor necrosis factor ⁇ receptors. monoclonal antibodies, polyclonal antibodies, antibody fragments, COX -2 inhibitors, metatioprotease inhibitors, such as FAPI, gtutamate antagonists, glial cell derived neurotrophic factors (GDNF), B2 receptor antagonists.
  • Substance P receptor (NKl ) antagonists Downstream regulatory element antagonistic modulator (DREAM), iNOS, inhibitors of t ⁇ trodotoxin (TTX)-resistant Na + channel receptor subtypes PN 3 and SNS2, inhibitors of interleuki ⁇ s, such as IL-1 , 1L-6, 1L-8 and IL-IO, TNF binding protein, dominant-negative TNF variants, Nanobodies®, kinase inhibitors, and combinations thereof.
  • Suitable therapeutic agents include but are not limited to Adalirouroab, Infliximab, Etanercept, Pegsunercept (I 1 EG sTNF-RI), Onercept Kineret®, sTNF-Ri, CDP-870, CDP-571.
  • Humanized anti-IL-o raAb MIlA, Tocilizumab, Chugai), HMGB- I raAb (Critical Therapeutics Inc.), anti-!L2R antibodies ⁇ dacliz ⁇ mab, basilicimab), ABX (anti IL-8 antibodies), recombinant human IL- IO, l ⁇ Max IL- 15 (aiiti ⁇ lL 15 antibodies) and combinations thereof.
  • Still other therapeutic agents include, but are not limited to, NF Kappa B inhibitors, such as glucocorticoids including clonidine; nonsteroidal antiinflammatory drugs (NSAIDs), such as salicylates, diflunisai, indom ⁇ thacin, ibuprofen.
  • NSAIDs nonsteroidal antiinflammatory drugs
  • naproxen, tolraetin, ketorolac, diclofenac, ketoprofe ⁇ , fenamates (meienamic acid. medofenamie acid), enoiic acids (piroxicani, nieloxicam), nabumeto ⁇ e, celecoxib, etodolac, nimesulide, apazone, gold, sulindac and tepoxalin; antioxidants, such as dithiocarbamate.
  • the therapeutic agent is an osteoinductive factor.
  • suitable osteoinductive factors include, but are not limited to, a bone morphogenetic protein, a growth differentiation factor or biologically active fragment or variant thereof, a LJM mineralization protein or biologically active fragment or variant thereof, or combinations thereof.
  • the one or more therapeutic agents within the drug depot implant may be incorporated into a sustained release pharmaceutical composition.
  • two or more therapeutic agents are incorporated into a sustained release pharmaceutical composition
  • two or more therapeutic agents are separately incorporated into separate biocompatible polymers
  • the invention also includes a drug depot implant for treating osteolysis and/or bone resorption comprising administering a drug depot implant to an osteolytic site in a subject in need of treatment, the drug depot implant providing an effective amount of a pharmaceutical composition comprising one or more therapeutic agents, wherein administration of the pharmaceutical composition is localized and sustained.
  • the one oi more therapeutic agents includes, at least one osteoinductive factor
  • suitable osteoinductive factors include a bone morphogenetic protein, a growth differentiation factor or a biologically active fragment thereof, a LlM mineralization protein or a biologically active fragment thereof, or combinations thereof.
  • a method for alleviating pain associated with bone tumors comprising administering to a tumor site in a subject in need of treatment a drug depot implant comprising an effective amount of one or more therapeutic agents, wherein administration of the composition is localized and sustained.
  • the one or more therapeutic agents includes at least one osteoinductive factor Suitable examples include, but are not limited to, a bone morphogenetic protein, a growth differentiation factor or a biologically active fragment or variant thereof, a IJM mineralization protein or a biologically active fragment or variant thereof or combinations thereof ⁇
  • a system for providing pain relief medication in a mammalian subject comprising a depot for providing controlled and directed delivery of at least one therapeutic agent to a target site in a subject in need thereof comprising an effective amount of a composition comprising at least one therapeutic agent which decreases inflammation at the target site.
  • the therapeutic agent further comprises a modified release pharmaceutical composition.
  • the system can further comprise two or more therapeutic agents
  • a catheter is provided rather than a depot.
  • a catheter has a proximal end and a distal end, the distal end having an opening to deliver a pharmaceutical in situ, the proximal end being fiddly connected to a pharmaceutical pump
  • the distal end of the catheter delivers the therapeutic agent within about 10 cm of, or closer to, the target site
  • the catheter delivers the therapeutic agent within about 5 cm of, or closer to, the target site in this system, the at least one therapeutic agent may inhibit inflammation mediated by TNF- ⁇ .
  • a therapeutic agent is a TNF- ⁇ receptor inhibitor, for example, a pegylated soluble TNF-u receptor
  • Other suitable therapeutic agents are listed herein.
  • the system may further comprise a therapeutically effective amount of at least one osteoinductive factor Suitable osteoinductive factors include, but are not limited to. a bone morphogenetic protein, a growth differentiation factor or a biologically active fragment or variant thereof, a LlM mineralization protein or a biologically active fragment or variant thereof, or combinations thereof.
  • a bone morphogenetic protein a growth differentiation factor or a biologically active fragment or variant thereof
  • a LlM mineralization protein or a biologically active fragment or variant thereof or combinations thereof.
  • the system of the invention employs a depot comprising a modified release pharmaceutical carrier
  • the invention also includes the use of a composition comprising one or more therapeutic agents that decrease inflammation at a target site for the manufacture of a pharmaceutical for reducing pain, wherein administration of an effective amount of the composition to a target site in a subject in need of treatment is localized and controlled.
  • the invention is a depot for alleviating pain and limiting bone loss associated with osteolysis, wherein the administration of the composition to an osteolytic site in a subject in need of treatment is localized and controlled lii
  • the invention includes the use of a composition comprising one or more therapeutic agents that decrease inflammation at a target site for the manufacture of a pharmaceutical for alleviating pain associated with bone tumors, wherein administration of the composition Io a tumor site in a subject in need of treatment is localized and controlled
  • the composition may he a sustained release pharmaceutical composition.
  • a method for retarding tissue necrosis and/or damage comprising administering to a target site in a subject in need of treatment an effective amount of a pharmaceutical composition comprising one or more therapeutic agents, wherein the one or more therapeutic agents are administered by a depot that provides localized and sustained release of the pharmaceutical composition.
  • the depot is implanted in a subject at or near a target site, such as, but not limited to, an inflamed nene or a spinal site, for example into a spinal disc or spinal disc space.
  • Radiographic marker on the drug depot implant to permit a surgeon to accurately position the implant into a tissue of a patient.
  • radiographic markers include, but are not limited to, barium, calcium phosphate, and metal beads.
  • Such radiographic markers will also permit the surgeon to track movement and degradation of the implant in the tissue over time
  • the surgeon may accurately position the implant in the tissue using any of the numerous diagnostic imaging procedures known to one of ordinary skill in the art
  • diagnostic imaging procedures include, for example, X-ray imaging or fluoroscopy.
  • Another aspect of the present invention provides for methods, systems and reagents comprising a drug depot implant configuration for providing a concentration gradient of the therapeutic agent to the tissue of a patient.
  • the preferred drug depot implant is a rod configuration that provides an optimal, therapeutically effecti ⁇ e amount of the therapeutic agent up to about 1 cm to about 5 cm from the rod.
  • Another aspect of the present invention provides for drug depot implant configurations comprising microspheres loaded with a therapeutic agent, such as a TNF- inhibitor, for targeted delivery' to a desired region of a patient.
  • a therapeutic agent such as a TNF- inhibitor
  • targeted drug depot delivery my be achieved by any means including for example, by injection either into the disc space, the spinal canal, or in the surrounding soft tissues.
  • This embodiment of the present invention delivers the therapeutic agent closer to the inflamed tissue, e g , nerve roots causing sciatic pain, nerve fibers growing into annular tears m discs causing back pain, or knee joints with osteoarthritis
  • a drug delivery device may he delivered by a wide variety of methods, such as by placement into a drill site, injection by syringe aud/oi catheter or forceful injection by gun
  • FIG. 1 is a cross-sectional view of one embodiment of a drug depot implant.
  • FIG. 2 is a cross-sectional view of an alternative embodiment of a drug depot implant
  • FIG 3 is a side view of another embodiment of a drug depot implant
  • FIG. 4 shows a targeted delivery device and a drug depot implant.
  • FIG. 5 is a side view of another drug depot implant.
  • FIG. 6 shows a drug depot implant with a first embodiment radiographic marker.
  • FIG. 7 shows a drug depot implant with a second embodiment radiographic marker.
  • FIG. 8 is a side view of an alternative embodiment of a drug depot implant.
  • Figure 9 illustrates the drug depot implant of FIG 9 deployed in a disk.
  • Figure 10 illustrates the drug depot implant of FlG. 8 deployed in a joint
  • Figure 1 1 is a side view of another drug depot implant.
  • Figure 12 is a side view of an alternative ding depot implant
  • Figure 13 is a side view of yet another alternative of a drug depot implant.
  • Figure 14 shows the daig depot implant of FIG. 1 1 deployed in a joint.
  • Figure 15 shows the drug depot implant of FIG 12 deployed in a joint.
  • Figure 16 is a side view of another drug depot implant.
  • Figure 17 shows the drug depot implant of FIG 16 and an associated targeted delivery system
  • Figure IS shows the drug depot implant of FlG. 16 deployed in a disc and surrounding soft tissue.
  • Figure 20 illustrates delivery of a therapeutic agent to a spinal canal and surrounding soft tissue utilizing microspheres.
  • Figure 21 illustrates delivery of a therapeutic agent to a synovia! cavity utilizing microspheres.
  • Figure 22 illustrates delivery of a therapeutic agem to soft tissue surrounding a spinal canal utilizing a gel
  • Figure 23 illustrates delivery of a therapeutic agent to soft tissue surrounding a spinal canal utilizing a gel with dispersed microspheres.
  • the present invention provides methods, systems and reagents for facilitating implantation of a drug depot implant into a subject comprising implanting an implant depot loaded with a therapeutic agent
  • the drug depot implants of the present invention may be designed for placement and location within oi near the synovial joint, the spinal disc space, the spinal canal or the surrounding soft tissue.
  • the present invention also provides methods, systems and regents for decreasing, eliminating, or managing pain, especially pain of neuromuscular or skeletal origin, by providing direct and controlled delivery, i.e., targeted delivery of at least one therapeutic, agent to one or more sites of inflammation and sources of pain.
  • a therapeutic agent itself may be on a continuum of rapid acting to long acting
  • the therapeutic agent is a component of a pharmaceutical composition which can range in a continuum of rapid release to sustained release.
  • the delivery of that pharmaceutical composition via the targeted delivery system of the invention can include, for example, rapid and repeating deliver ⁇ .' at intervals or continuous deliver ⁇ -. The delivery can be "local,” "direct.” and "controlled.”
  • a drug depot implant of the present invention comprises a physical structure to facilitate implantation and retention in a desired location of a subject, such as for example, a synovial joint, a disc space, a spinal canal or a tissue of a subject, and a therapeutic agent that provides a concentralion gradient for targeted delivery of the therapeutic agent to the location
  • the implant of the present invention provides an optimal drug concentration gradient of the therapeutic agent at a distance from about ! cm to about 5 cm from the implant.
  • the implant of the present invention may further comprise an insertion cannula for delivery of the therapeutic agent to the subject.
  • One aspect of the present invention provides a depot attached to a probe, wherein the probe is released by a pull-back mechanism for delivery of the therapeutic agent to the subject.
  • the implant of the present invention may further comprise one or more barbs for minimizing migration of the implant in a tissue of a subject.
  • the implant of the present invention may still further comprise a cap for retaining the depot in a tissue membrane or between tissue planes
  • An aspect of the present invention provides an injectable drug depot implant comprising microspheres loaded with a therapeutic agent, wherein the microspheres are injected into a synovial joint, a disc space, a spinal canal, or a soft tissue surrounding the spinal canal.
  • a daig depot implant comprising a gel in viscous form and microspheres loaded with a therapeutic agent, wherein the combination of gel and microspheres are positioned into a synovial joint disc space, a spinal canal, or a soft tissue surrounding the spina! canal of a subject.
  • the gel is a sprayable or injectable adherent gel that solidifies upon contact with tissue
  • the viscous gel loaded with microspheres also delivers the microspheres to the desired inflamed tissue location and prevents the microspheres from being removed from that area by the venous systemic vasculature or otherwise dispersed too widely to get the desired therapeutic effect.
  • the gel may be absorbed, thereby allowing the microspheres to begin releasing the therapeutic agent.
  • the microspheres do not begin releasing the agent until they are released from the gel. So, the microspheres must be formed from something that is insoksable or inert in the gel, but soluable or aethe once it comes into contact with the targeted tissue.
  • the gel must be something that dissolves or disperses within the subject tissue As the gel begins to dissolve within hours to days, the microspheres are exposed to body fluids and begin releasing their contents.
  • Examples of gels could be gelatin, PEG, or POE So, the gel could be a different material from the microspheres or the same material, i.e , POE.
  • the gel and microspheres are formulated to optimize exposure time of the tnicospheres and release of the therapeutic agent from the microspheres.
  • the present invention provides numerous designs for the drug depot
  • One aspect of the invention provides that when depot barbs are employed they can be oriented in one direction to facilitate implantation while also preventing backing out or expulsion of the depot from the desired tissue location.
  • the barbs could also be oriented in opposite directions to prevent movement in either direction once implanted
  • Another aspect of the invention provides that the barbs could be fixed protrusions or flexible protrusions that deflect out once implanted
  • a joint capsule depot has barbs in combination with a cap such that once the depot is inserted into the wall of the joint capsule the barb deploys and holds the depot in place via the cap and deployed barbs
  • the barbs keep the depot from backing out and the cap keeps it from completely going into the joint space.
  • the depot can be designed such that the therapeutic agent is embedded only in the portion of the depot protruding into the joint space synovial fluid, hi this aspect of the invention as the joint articulates it facilitates the distribution of the therapeutic agent throughout the synovial fluid In one embodiment, after 3-6 months the depot completely degrades and no longer transverses the joint capsule.
  • radiopaque marks are positioned in the depot at opposite ends of the depot to assist in determining the position of the depot relative to the inflamed tissue to be treated.
  • the radiopaque marker could be a spherical shape or a ring around the depot.
  • the present invention contemplates the use of rod-shaped depots in joint capsules, in which the depots contain one or more sutures for retaining the depot up against the inside of the joint capsule.
  • the present invention also presides a depot shaped as a tapered rod with a hullet- shaped tip to ease insertion of the depot through the joint capsule tissue and minimize tissue disruption.
  • the depot may contain a suture that is embedded into a biodegradable rod during manufacture of the depot.
  • the suture is strategically positioned within the rod to facilitate positioning the depot adjacent to the inside of the joint capsule
  • a very small hole is made in the John capsule with a blunt probe, then the tapered rod is slowly pushed through this hole, slowly stretching the tissues apart to minimize tissue tearing. Once the rod is fully inserted, the hole in the joint capsule closes upon itself.
  • the suture embedded in the rod is left transversing through the capsule so that it can be pulled taut and knotted up against the outside of the joint capsule, forcing the depot up against the inside of the joint capsule Having the depot up against the inside of the joint capsule will prevent the depot from interfering with normal joint motion.
  • the suture can exit through the ends of the rod, in the middle, or somewhere in-between.
  • the suture can exit through just one hole through the joint capsule or through two or more holes
  • the suture exits the rod at two points near the ends of the rod and passes through two points in the joint capsule.
  • Another aspect of the present invention provides several designs that are contemplated for use in the mtervetebral disc and joint capsules, which includes bead- shaped depots strung together along a suture
  • the beads may be a drug-loaded biodegradable polymer
  • the suture may be either degradable or non-degradable material
  • One embodiment of the invention provides at the leading end of the suture an optional needle or barb to retain the strand within the disc or joint capsule.
  • the strand may be implanted by inserting a cannula, which contains the strand of beads, inside the disc, joint, or soft tissue as far as desired, then deploying the barb into the soil tissue ⁇ e.g , the annulus) and slowly retracting the cannula, which will result in the string of beads being pulled from the cannula
  • a cannula which contains the strand of beads
  • the beads are retained at the location where the datg is desired inside a disc, along a nerve root, or transverse across a joint, resulting in a more uniform distribution of the drug.
  • the string of drug-eluti ⁇ g bead depots are disposed along the route of inflamed tissue, thereby resulting in a more effective distribution of the drug and greater clinical effectiveness.
  • a very small hole may be made in an intervertebral disc at the site of a possible disc herniation or in a joint capsule with a blunt probe through which a cannula may he inserted to implant the string of beads.
  • Another aspect of the present invention provides a method for delivering a therapeutic agent to a synovial joint disc space, a spinal canal, or a soft tissue surrounding the spinal canal of a subject, comprising inserting within the synovial joint, the disc space, the spinal canal, or the soft tissue surrounding the spinal canal of a subject, a drug depot implant comprising a hollow depot, the hollow depot comprising a therapeutic agent that provides a concentration gradient for targeted delivery of the agent to the synovia! joint, the disc space, the spinal canal, or the soft tissue surrounding the spinal canal of a subject.
  • a drug depot implant comprising a hollow depot, the hollow depot comprising a therapeutic agent that provides a concentration gradient for targeted delivery of the agent to the synovia! joint, the disc space, the spinal canal, or the soft tissue surrounding the spinal canal of a subject.
  • One embodiment of the invention provides for an optima! drug concentration gradient extending about 1 cm to about 5 cm from the implant.
  • Another embodiment of the present invention provides for delivering the therapeutic agent to the synovial joint
  • Another embodiment of the present invention provides for the drug depot implant further comprising a barb for minimizing migration of the implant in a tissue of a subject, and further comprising a cap for retaining the depot in a tissue membrane or between tissue planes.
  • Another aspect of the present invention provides a method for delivering a therapeutic agent to a synovial joint, disc space, a spinal canal, or a soft tissue surrounding the spina! canal of a subject, comprising inserting within the synovia! joint the disc space, the spinal canal, or the soil tissue surrounding the spinal canal of a subject a drug depot implant comprising microspheres, the microspheres comprising a therapeutic agent that provides a concentration gradient for targeted delivery of the agent to the subject, wherein the microspheres are injected into the synovia! joint, the disc space, the spina! canal, or the soft tissue surrounding the spinal canal.
  • Another aspect of the present invention provides a method for delivering a therapeutic agent to a synovial joint, a disc space, a spinal canal, or a soft tissue surrounding the spinal canal of a subject, the method comprising inserting within the synovial joint, the disc space, the spinal canal, or the soft tissue surrounding the spinal canal of a subject a drug depot implant comprising a gel in viscous form and microspheres loaded with a therapeutic agent.
  • a drug depot implant comprising a gel in viscous form and microspheres loaded with a therapeutic agent.
  • the combination of gel and microspheres are positioned into the synovia! joint, the disc space, the spinal canal, or the soft tissue surrounding the spinal canal of a subject
  • the gel is a sprayable or injectable adherent gel that hardens upon contact with tissue.
  • drag delivery device is an art-recognized term and refers to any medical device suitable for the application of a drug to a targeted organ or anatomic region.
  • the term includes those devices that transport or accomplish the instillation of the compositions towards the targeted organ or anatomic area, even if the device itself is not formulated to include the composition
  • a needle or a catheter through which the composition is inserted into an anatomic area or into a blood vessel or other structure related to the anatomic area is understood to be a drug delivery device.
  • a stent or a shunt or a catheter that has the composition included in its substance or coated on its surface is understood to be a drug deliver)' device
  • a drug delivery device can include a rigid or flexible container.
  • a drug delivers' device may also include a semi-solid composition that releases the daig by dissolution of the device or by leaching of drug from the device.
  • “implant” covers attaching to the joint in any way, e.g., by implanting into a cavity in bone or cartilage or by suturing or otherwise adhering the device to the surface of bone, tendon, or cartilage.
  • microspheres' * shall mean generally spherical particles about IO m to about 100 m in size
  • Microspheres comprise a hollow space encapsulated by lipids, polymers, at least one surfactant, or any combination thereof, wherein the hollow space comprises a therapeutic agent.
  • microspheres may include microb ⁇ bbles and liposomes.
  • osteoinduc ⁇ on refers to the ability Io stimulate the proliferation and differentiation of piuripotent mesenchymal stem cells (MSCs)
  • MSCs piuripotent mesenchymal stem cells
  • stein cells differentiate into cbondrafolasts and chondrocytes, laying down a cartilaginous KCM, which subsequently calcifies and is remodeled into lamellar bone.
  • the stem cells differentiate directly into osteoblasts, which form bone through direct mechanisms. Osteoinduction can be stimulated by osteogenic growth factors, although some ECM proteins can also drive progenitor cells toward the osteogenic phenotype.
  • the term "patient,” “SUbJeCt,” or “host” refers to a biological system to which a treatment can be administered.
  • a biological system can include, for example, an individual cell, a set of cells (e.g., a cell culture), an organ, or a tissue.
  • the term '"patienf can refer to animals, including, without limitation, humans,
  • a targeted delivery' system is a direct and local administration system to deliver therapeutic agents and includes, but is not limited to. a depot, or a system administered locally by insertion of an implant, catheter or syringe at or near a target site.
  • the catheter or syringe is optionally operably connected to a pharmaceutical delivery pump. It is understood that pumps can be internal or external as appropriate
  • a “depot” includes., but is not limited to, capsules, microspheres, particles, gels in viscous forms, coatings, matrices, wafers, pills or other pharmaceutical delivery compositions
  • a depot may comprise a biopolymer that is either biodegradable or nco-degradahie
  • a “therapeutically effective amount” is such that when administered, the agent results in alteration of the biological activity, such as, for example, inhibition of inflammation
  • the dosage administered to an individual will vary depending upon a variety of factors, including the agent ' s pharmacokinetic properties, the route of administration, patient conditions and characteristics (sex, age, body weight, health, size, etc.), extent of symptoms, concurrent treatments, frequency of treatment and the effect desired. Adjustment and manipulation of established dosage ranges are well within the ability of those skilled in the art. as well as in vitro and in vivo methods of determining the alteration of biological activity in an individual, such as the inhibition of TNF or IL-I .
  • the therapeutic agent is used in an amount typically ranging between about 0.1 to 5000 ⁇ g/kg of body weight or about 1 to SOOO ⁇ g/kg of body weight. Amounts of about SO to 500 ⁇ g/kg of body weight are preferred, and amounts of about 50 to 250 ⁇ g/kg of body weight are further preferred.
  • the term "treating" or '"treatment" of a disease refers to executing a protocol, which may include administering one or more drugs to a patient (human or otherwise), in an effort to alleviate signs or symptoms of the disease. Alleviation can occur prior to signs or symptoms of the disease appearing, as well as after their appearance Thus, “treating" or “treatment” includes “preventing” or "prevention” of disease.
  • “treating” or “treatment” does not require complete alleviation of signs or symptoms, does not require a cure, and specifically includes protocols that have only a marginal effect on the patient.
  • “Localized” delivery is defined herein as non-systemic delivery wherein one or more therapeutic agents are deposited within a tissue, for example, a nerve root of the nervous system or a region of the brain, or in close proximity (within about 10 cm, or preferably within about 5 an, for example) thereto.
  • “Targeted deliver)' system” pros ides delivery of one or more therapeutic agents in a quantity of pharmaceutical composition that can be deposited at the target site as needed for pain, either continuously or at an intermittent rate.
  • therapeutic agents refers to pharmacologically active substances, such as those that are direct- and local-acting modulators of pro-inflammatory cytokines such as " TNF- ⁇ and IL-I including but not limited to, for example, soluble tumor ⁇ e ⁇ osis factor ⁇ receptors, any pegylated soluble tumor necrosis factor u iccepior, monoclonal or polyclonal antibodies or antibody fragments or combinations thereof.
  • Suitable therapeutic agents include receptor antagonists, molecules that compete with the receptor for binding to the target molecule, antisense polynucleotides, and inhibitors of transcription of the DNA encoding the target protein.
  • Suitable examples include but are not limited to Ada! imumab. Infliximab, Etanercept, Pegsunercept (PEG sTNF-Ri), sTNF-Ri, CDP-870, CDP-571, CNI-1493, RDP58, ISlS 104838, l -*3- ⁇ -D- giucans, Lenercept. S ⁇ G-sI NFRII FC Mutein. D2E7, Afelimomab, and combinations thereof.
  • these substances can decrease pain through their actions as inhibitors or agonists of the release of pro-inflammatory molecules
  • these substances can act by inhibiting or antagonizing expression or binding of cytokines or other molecules that act in the early inflammatory cascade, often resulting in the downstream release of prostaglandins and leukotrienes.
  • These substances can also act, for example, by blocking or antagonizing the binding of excitatory molecules to nociceptive receptors in the nervous system or neuromuscular system, as these receptors often trigger an inflammatory 10 response to inflammation or injury of the nerve or surrounding tissue through a nitric oxide-mediated mechanism
  • These therapeutic agents include, for example, inhibitors of the action of tumor necrosis factor alpha (TNF ⁇ ).
  • therapeutic agents such as anti-TNF agents are particularly effective for joint pain, for example, because they not only decrease the inflammation that provides the source of pain but also slow the progression of joint destruction that may accompany the inflammatory response Hence, local targeted delivery of the therapeutic agents in accordance with the invention may reduce tissue necrosis' and damage
  • Inflammation can be an acute response to trauma or a chronic response to the presence of inflammatory agents.
  • TNF - ⁇ attaches to cells to cause them to release other cytokines that cause inflammation.
  • the purpose of the inflammatory cascade is to promote healing of the damaged tissue, but once the tissue is healed the inflammatory process does not necessarily end. Left unchecked, this can lead to degradation of surrounding tissues and associated chronic pain. Thus, pain can become a disease state in itself. That is, when this pathway is activated, inflammation and pain ensue. Often a vicious and seemingly endless cycle of insult, inflammation, and pain sets in.
  • Examples ⁇ f conditions in which this cycle is present include, but are not limited to, rheumatoid arthritis, osteoarthritis, carpal tunnel syndrome, lower back pain, lower extremity pain, upper extremity pain, tissue pain and pain associated with injury or repair of cervical, thoracic, and/or lumbar vertebrae or intervertebral discs, rotator cuff, articular joint. TMJ, tendons, ligaments, and muscles.
  • TNF is both affected by upstream events that modulate its production and, in turn, affects downstream events
  • therapeutic agents are designed to specifically target INF as well as molecules upstream, downstream, and/ or a combination thereof.
  • Such approaches include, but are not limited to modulating TNF directly, modulating kinases, inhibiting cell-signaling, manipulating second messenger systems, modulating kinase activation signals, modulating a cluster designator on an inflammatory cell, modulating other receptors on inflammatory cells, blocking transcription or translation of TNF or other targets in pathway, modulating TNF- ⁇ post-translational effects, employing gene silencing, and modulating i ⁇ tedeukins, for example ⁇ L- 1.
  • inhibitors ranges from initiating to shutting down, and within that range is included enhancing significant! ⁇ or slightK to inhibiting significant!) OT slightly
  • inhibiting includes a dowiueguiation which ma> i educe or eliminate the targeted function, such as the production of a protein or the translation of an oligonucleotide sequence
  • a given patient's condition may require only inhibition of a single molecule, such as TNF. or modulating rnoie than one molecule in a cascade of upstream and or downstream events in the pathway
  • TNF- ⁇ inhibitors reduce chronic discogenic back and !eg pain if delivered fa> perispinal administration
  • a therapeutic agent is a C 0X2 inhibitor
  • Cyclooxygenase inhibitors are a class of enzymes that are believed to iegulate the synthesis of prostaglandin E2 ⁇ PGE2j PGE2 may increase discogenic back pain b> inducing radioculopatln Inhibiting COX enzymes sen es to reduce low back pain
  • COX enzymes are iegulators of PGH2s
  • COX2 inhibitors reduce low back pain by decreasing PGF-2 production
  • One suitable C0X2 inhibitor (6-mcth ⁇ xy-2-na ⁇ thylacetic acid) has been shown to suppress PGF.2 production and local inflammation in cell culture as decribcd by M el arange «.'/ ⁇ ?/.
  • T ⁇ PI is a metalloprotease inhibitor ⁇ hich can block clea ⁇ age of I NF- ⁇ which, in turn, will reduce production of TNK-u
  • Still othei suitable therapeutic agents include glutamate antagonists, glial cell- derived neurotropic factors (GDNF), B2 receptor antagonists, Substance P receptor ⁇ NKl ⁇ antagonists such as capsaicin and en amide, Dow nstream regulatory element antagonistic modulator (DREAM), ⁇ NQS, inhibitors of tetrodotoxin (TTX)-resistam Na * -channel receptor subtypes PN3 and SNS2, inhibitors of imerlcukins such as 11. -1.
  • glutamate antagonists glial cell- derived neurotropic factors (GDNF), B2 receptor antagonists, Substance P receptor ⁇ NKl ⁇ antagonists such as capsaicin and en amide, Dow nstream regulatory element antagonistic modulator (DREAM), ⁇ NQS, inhibitors of tetrodotoxin (TTX)-resistam Na * -channel receptor subtypes PN3 and SNS2, inhibitors of imerlcukins such as 11. -1.
  • the therapeutic agent is a TNF binding protein
  • One suitable such therapeutic agent is currently referred to as Onercept formulae including Oneicept, Oneicept-like agents, and deiivatn es a*e all consid ⁇ ed acceptable
  • Still other suitable therapeutic agents include dominant-negative TNi : variants
  • a suitable dominant-negative TNF variant includes but is not limited to DK-TNF and including those described by Steed et aL (2003 K 'inactivation of TNF signaling b ⁇ rationally designed dominant-negame FNF v ariants; ' Science, 301(5641) 1895-189S
  • Still more embodiments include the use of a recombinant adeno-associated ⁇ iral (rA ⁇ V) ⁇ ector technolog ⁇ platform to deliver oligonucleotides encoding inhibitors, enhancers, potentiators, neutraliz
  • therapeutic agents that inhibit kinases and/or inhibit cell signaling aie employed Therapies that fall in this catego ⁇ aie capable of manipulating the second messenger s> stems Kinase actuation signals multiple downstream effectors, including those involving phosphatidylinositol 3-kinase and mitogen-actnated protein kinases (MAPK), p38 MAPK.
  • MAPK mitogen-actnated protein kinases
  • Src and protein tyrosine kinase One example includes the signaling of TNF 1 Gt effects is the downstream activation of MAPK
  • kinase inhibitors are Glee ⁇ ec, liercepiin, ⁇ ressa, imatinib (S 11571 ), herbimycin A, tyrphostin i 7 . erbstatin, geissem, statsrosporine. PD98O5*3, SB203580,
  • Therapeutic agents that inhibit TNF- ⁇ post-translational effects are useful in the invention
  • the initiation of TNF-u signaling cascade results in the enhanced production of numerous factors that subsequently act in a paracrine and autocrine fashion to elicit further production of TNF- ⁇ as well as other pro-inOamniaiory agents (e.g , IL-I, 1L-6, IL-S, HMG-B I)
  • Extracellular TNF- ⁇ modifying therapeutic agents that act on the signals downstream of TNF- ⁇ are useful in treating systemic inflammatory diseases
  • Some of these therapeutic agents are designed to block other effector molecules while others block the cellular interaction needed to further induce their production, for example, integrins and eel! -adhesion molecules.
  • Suitable therapeutic agents include' integrin antagonists, alpha-4 beta-7 integrin antagonists, ceil adhesion inhibitors, interferon gamma antagonists, CTLA4-lg agonists 'antagonists (BM S-! 88667), CD40 ligand antagonists.
  • Interleukin-i is a pro- inflammatory cytokine similar in action to TNF- ⁇ .
  • certain inhibitors of this protein are similar to those developed to inhibit TNF- ⁇ .
  • One such example is Kineret €* Canal ⁇ nra) which ia a recombinant, no ⁇ -giycosylated form of the human inerieuk ⁇ n-t receptor antagonist (IL-I Ra).
  • AMG 108 is a monoclonal antibody that blocks the action of IL- 1
  • pain can become a disease state in itself
  • One particular area in which this is particularly true is in the lower back and legs.
  • disk herniation is a major cause of back pain and sciatica Sciatica, or radiculopathy, is pain that radiates down the back of the iegs and is generally thought to he caused by irritation of the roots of the sciatic nerve.
  • Back pain can also be caused by spinal stenosis, characterized by overgrowth of bony or soft tissue in the spinal canal with associated pressure on the adjacent nerves. Degeneration of the facet joints between the vertebrae, tumors, infections, fractures, and inflammation of surrounding soft tissues can also cause back pain
  • a sustained dosage that is readily available for delivery at regular intervals, continuously, or as needed to manage the inflammatory response.
  • This dosage can be provided, for example, by means of a controlled administration system.
  • Excitatory amino acids such as giutamate and aspartate have been shown to play a role in the development of pain originating from nerves Mice with blocked giutamate receptors, for example, have been shown to have a reduction in their responses to pain.
  • Giutamate binds to two major classes of receptors, inotropic giutamate receptors (ligand-gated ion channels) and metabotropic receptors ⁇ G -protein-coupled receptors).
  • the inotropic receptors in the spinal cord include the N-r ⁇ ethyl-D-aspartie acid (NMDA) receptors, the tt-amino-3-hydroxy-5-methyl-4-isoxazole ⁇ ropionate (AMPA) receptors, and the kainite receptors.
  • NMDA N-r ⁇ ethyl-D-aspartie acid
  • AMPA tt-amino-3-hydroxy-5-methyl-4-isoxazole ⁇ ropionate
  • kainite receptors kainite receptors.
  • one or more therapeutic agents can include, for example, antagonists or inhibitors of giutamate binding to NMDA receptors, AMPA receptors, and/or kainate receptors.
  • Interleukin- 1 receptor antagonists thalidomide (a TNF- ⁇ release inhibitor), thalidomide analogues, (which reduce TNF- ⁇ production by macrophages), bone morphogenetic protein (BMP) type 2 and BMP-4 (inhibitors of caspase 8, a TNF- ⁇ activator), quinapril (an inhibitor of angiotensin II, which upreguiates TNF- ⁇ ), interferons such as IL-1 1 (which modulate TNF- ⁇ receptor expression), and aur ⁇ n-tricarboxylie acid (which inhibits TNF- ⁇ ). for example, may also be useful as therapeutic agents for reducing inflammation It is contemplated that where desirable a pegylated form of the above may be used.
  • NF kappa B inhibitors such as glucocorticoids, including clonidine, antioxidants, such as dilhiocarbamate, and other compounds, such as sulfasalazine [2-hydroxy-5-[-4-[c2- pyridinylamino]sulfonyi]azo]benzoic acid].
  • Suitable therapeutic agents include NSAIDs 5 such as tepoxalin, salicylates, difiuiiisaL i ⁇ doroethacin, sulindac, ibuprofen, naproxen, tohnetin, ketorolac, diclofenac, ketoprofen, fenamates (mefenarnic acid, meclofenamic acid), enolic acids (piroxicam, roeloxtcaro), ⁇ abumetone. celecoxib, etodolac, nirnesuiide. apazone and gold; other examples include steroids, such as Cortisol, cortisone, hydrocortisone. fludrocortisone, prednisone, prednisolone, meihylprednisolone, triamcinolone, betamethasone, dexamethasone. beclomethasone and fluticasone.
  • NSAIDs 5 such as te
  • the invention may further provide an implant comprising a pharmaceutical composition comprising one or more biopolymers and at least one therapeutic agent.
  • Example biopolymers include, but are not limited to, poiy(alpha-hydroxy acids), poly(lactide-co-glycoiide) (PLGA), polyiactide (PLA), polyglycolide (PG), polyethylene glycol (PI ⁇ XT) conjugates of poly(alpha ⁇ hydroxy acids), polyorthoesters, polyaspirins, polyphosphagenes, collagen, starch, chitosans, gelatin, alginates, dextrans, vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBT copolymer
  • polyphosphates polycaprolactones, polytrimethylene carbonates, polydioxanones, polyamidc-esters, polyketals, polyacevals, glycosaminoglycans, hyaluronic acid, hyaluronic acid esters, polyethylene- vinyl acetates, silicones, polyurethanes, polypropylene fumarates, polydesami ⁇ otyrosine carbonates, polydesaminotyrosi ⁇ e arylates. polydesami ⁇ otyrosine ester carbonates, polydesamnotyrosine ester arylates, polyethylene oxides, polyorthocarbo ⁇ ates, polycarbonates, or copolymers oi physical blends thereof or combinations thereof.
  • the biopoWmer may also provide for non-immediate (i.e., sustained) release.
  • sustained-release biopolymers include, but are not limited to, poly(alpha-hydroxy acids), ⁇ oly(lactide-co-glycolide) (PiGA), polyiactide (PLA), poiygiycoiide (PG), polyethylene glycol (PEG) conjugates of poly ⁇ alpha-hydro.xy acids), polyorthoesters, polyaspirins.
  • polyphosphagenes collagen, starch, chitosans, gelatin, alginates, dextrans, vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA,
  • PEGT-PBT copolymer (poiyactive), methacrylates, poly(N-isopropyiacrylamide), PEO- PPO-PEO (piuronics), PEO-PPO-PAA copolymers, PLGA-PEO-PLGA, or combinations thereof.
  • the present invention also contemplates that a gel may be utilized with the drug depot implant, provided that the gel has a consistency sufficient to hold the therapeutic agent, i.e., be in a viscous form.
  • the therapeutic agent such as for example BMP, may be provided in freeze-dried form and reconstituted in collagen gel. or any other suitable gel carrier. Any suitable gel carrier capable of delivering the therapeutic agent to the target is contemplated
  • the dosage is provided by means of a drug depot implant. implanted to provide the dosage at, or in close proximity to, the target site.
  • a pharmaceutical composition comprises at least one therapeutic agent, as part of a drug depot implant and optionally diluents, excipients and other pharmaceutically acceptable agents desirable for improved stability, manufacturing, efficacy and the like
  • the targeted delivery system be able to accurately, precisely and reliably deliver the intended amount of drug over the intended period of time.
  • Many therapeutic agents are quite expensive, especially those formulated to retain stability and efficacy over extended periods of time.
  • ⁇ t is desirable that the pharmaceutical compositions suitable for targeted delivery systems of the instant invention be carefully formulated for the desired medical effect in a controlled, local and direct manner
  • the drug itself may be on a continuum of rapid acting to long acting.
  • the pharmaceutical composition itself can range in a continuum of rapid release or sustained release.
  • the options for deliver)- of that pharmaceutical composition is on a continuum and includes but is not limited to rapid and repeating deliver)' at intervals ranging to continuous delivery Delivery may occur at a desired site over a desired period of time for adequate distribution and absorption in the patient
  • the deliver)' is capable of being directed to sites that are deep, complicated, painful or dangerous to reach by conventional means and /or otherwise inaccessible.
  • the terms "a” and “an” are intended to include the singular as well as plural
  • the invention provides localized deliver)' in a controlled manner, such as that provided by the targeted delivery system of the invention
  • the continued up and down cycling of therapeutic agent levels in. the patient can be avoided, allowing the body to adjust more easily to the level of the therapeutic agent. Side effects can therefore be minimized
  • the targeted delivery system of the invention may additionally include, for example, an infusion pump that administers a pharmaceutical composition through a catheter near the spine or one or more inflamed joints, an implantable mini-pump that can be inserted at an inflammatory site or site of injury or surgery, an implantable control! ed- release device (such as, for example, the device described in United States Patent Number 6,001,386), and a sustained -release delivery system (such as the system described in United States Patent Number 6,007,843 ).
  • an infusion pump that administers a pharmaceutical composition through a catheter near the spine or one or more inflamed joints
  • an implantable mini-pump that can be inserted at an inflammatory site or site of injury or surgery
  • an implantable control! ed- release device such as, for example, the device described in United States Patent Number 6,001,386
  • a sustained -release delivery system such as the system described in United States Patent Number 6,007,843 .
  • the pharmaceutical composition can also be administered in a controlled and sustained manner by implanting the desired one or more therapeutic agents dispersed within a depot such as polymer matrix that breaks down over time within the tissues, or otherwise incorporated within a protective coating that provides for the delay of the release of the one or more therapeutic agents
  • a suitable pump is the SynchroMed* (Medtronic, Minneapolis, Minnesota) pump This pump has three sealed chambers One contains an electronic module and battery. The second contains a peristaltic pump and drug reservoir. The third contains an inert gas. which provides the pressure needed to force the pharmaceutical composition into the peristaltic pump.
  • the pharmaceutical composition is injected through the reservoir fill port to the expandable reservoir
  • the inert gas creates pressure on the reservoir, and the pressure forces the pharmaceutical composition through a filter and into the pump chamber
  • the pharmaceutical composition is then pumped out of the device from the pump chamber and into the catheter, which will direct it for deposit at the target site.
  • the rate of delivery of pharmaceutical composition is controlled by a microprocessor This allows the pump to be used to deliver simi lar or different amounts of pharmaceutical composition continuously, at specific times, or at set intervals between deliveries.
  • Potential drug delivery devices suitable for adaptation for the method of the invention include but are not limited to those described, for example, in United States
  • Patent Number 6,551 ,290 Elsberry, ci aiX which describes a medical catheter for target specific drug delivery
  • United States Patent Number 6,571,125 ⁇ Thompson ⁇ which describes an implantable medical device for controllably releasing a biologically active agent
  • United States Patent Number 6,594,880 Eisberry
  • iniraparenchymal infusion catheter system for delivering therapeutic agents to selected sites in an organism
  • United States Patent Number 5,752,930 (Rise, et al ), which describes an implantable catheter for infusing equal volumes of agents to spaced sites.
  • the polymers of the present invention may be employed in the preparation of extended-release or sustained release compositions for use in the method of the present invention
  • further exc ⁇ pients are employed
  • the amount of excipient that is useful in the composition of this invention is an amount that serves to uniformly distribute the active agent throughout the composition so that it can be uniformly dispersed when it is to be delivered to a subject in need thereof. It may serve to dilute the therapeutic agent to a concentration at which the therapeutic agent can provide the desired beneficial palliative or curative results while at the same time minimizing any adverse side effects that might occur from too high a concentration It may also have a preservative effect. Thus, for a therapeutic agent that has high physiological activity, more of the excipient will be employed.
  • the amount of excipient in the composition will be between about 50% weight (w) and about 99.9% weight of the total composition
  • the amount will be between about 98 0% and about 90.O 1 J-O weight of the total composition
  • therapeutic agents to decrease or eliminate pain in a human or animal subject by the method and systems of the present invention can be effective for alleviating pain, although amounts of any one or more therapeutic agents administered to a particular subject are at least one order of magnitude iess than those amounts of therapeutic agents, such as TNF- ⁇ inhibitors oi antagonists., thai are provided to individuals who undergo systemic infusion or injection
  • therapeutic agents such as TNF- ⁇ inhibitors oi antagonists., thai are provided to individuals who undergo systemic infusion or injection
  • the amount of therapeutic agents that must be administered in relation to conventional modes of administration, such as oral or by injection is decreased This increases the pharmaceutical efficiency of the therapeutic agent, because it is being directed to the tissue in which its action will provide the greatest effect, such as a nerve root or region of the brain.
  • While systemic delivery or delivery by intravenous injection may prov ide a sufficient level of therapeutic agent to produce the desired result, it also results in an increased risk of unwanted side-effects, such as risk of infection when anti-TNF- ⁇ compositions are repeatedly administered, thus resulting in increases in cost, inconvenience and discomfort to the patient.
  • Effective dosages for use in the method of the present invention can he determined by those of skill in the art, particularly when effective systemic dosages are known for a particular therapeutic agent Dosages may typically be decreased by at least 90% of the usual systemic dose if the therapeutic agent is prov ided as in the method and systems of the present invention.
  • the dosage is decreased by at least 75%, at least 80%, or at least 85% of the usual systemic dose for a given condition and patient population.
  • Dosage is usually calculated to deliver a minimum amount of one or more therapeutic agents per day. although daily administration is not required. If more than one pharmaceutical composition is administered, the interaction between the same is considered and the dosages calculated Intrathecal dosage, for example, can comprise approximately 10% of the standard oral dosage. Alternatively, an intrathecal dosage is in the range of about 10% to about 25% of the standard oral dosage.
  • Hie targeted delivery system of the invention can be positioned to deliver at the site of injury which is causing or will cause inflammation, such as a surgical site, or within about 0 5 to about 10 cm, or preferably less than 5 cm, for example, of the injury or inflammatory site.
  • This site can comprise one or multiple sites in the spine, such as between the cervical, thoracic, or lumbar vertebrae, or can comprise one or multiple sites located within the immediate area of inflamed or injured joints, such as the shoulder, hip, or other joints
  • Implantation of the drug depot implant can occur simultaneously with surgery to repair a fracture, remove a tumor, etc- , or can be performed in individuals who experience pain, especially chronic pain, as the result of earlier trauma, injury, surgery, or other initiation of inflammation.
  • a targeted delivery system comprises an interbody pump and a catheter, the catheter having a proximal end and a distal end, the distal end having an opening to deliver a pharmaceutical composition in sttu, and a proximal end of the catheter being fluidly connected to the interbody pump.
  • Tuning of doses can also be determined by a physician or other appropriate health care professional, or the patient, based upon the condition, for example, severity and d urati on of pain Durati on of admi ni strati on of therapeuii c agents, i nterval between d oses, size of dose, continuity or spontaneity of dosage administration, are all appropriately determined by an individual's physician.
  • the health care professional has options such as administering to a target site in a patient an effective amount of a pharmaceutical composition comprising one or more therapeutic agents, wherein the one or more therapeutic agents are administered by a targeted delivery' system.
  • the administration can (I j be localized and sustained, (2) occur over a period of at least one day to about 6 months, (3) be continuous or periodic. Further, the health care provider has the choice of selecting a pharmaceutical composition having a targeted release rate. For example, a targeted release rate is from about 24 hours to about 62 days.
  • the health care provider may vary the combinations as the patient provides feedback over the treatment course Accordingly, the health care provider lias numerous options not previously available, especially in the treatment of pain, particularly chronic pain
  • Hie methods, systems and reagents of the present invention may have both human medical and veterinary use, being suitable for use in human children and adults, as well as in other mammals.
  • Implantable controlled-delivery devices or compositions containing therapeutic agents as described herein can be placed during orthopedic surgery to minimize inflammation and associated pain and to decrease the stimulus mat often results in chronic pain, which becomes a disease state in itself
  • the targeted delivery system and method of the invention may be useful for decreasing pain associated with orthopedic surgery or injury, or orthopedic or neurological damage associated with infection or inflammation.
  • the method may be especially beneficial for larger animals such as horses, or smaller domestic pets such as cats and dogs
  • the controlled administration system and method of the invention can be used to alleviate pain associated with rotator cuff injury or repair, articular joint pain or repair, temporomandibular joint disorder, tendonitis, rheumatoid and osteoarthritis, carpal tunnel syndrome, ligament pain or repair, or targeted muscular pain relief, for example.
  • Examples of clinical indications for which the invention is appropriate include acute and chronic back and leg pain, whatever the origin.
  • the therapeutic agent is delivered in the vicinity of an irritated ner ⁇ e root at dose lower than current drug dosages
  • the therapeutic agent could be delivered over a period of a few days to several months, depending upon the clinical indication
  • This directed and controlled delivery is beneficial as certain drugs, for example TNF-inhibitors, act to reduce the infection fighting capability of the immune system and therefore can lead to infection and other adverse events.
  • Minimizing the amount of drug (in this case therapeutic agent) and targeting a site of delivery is a significant ir ⁇ pros ement o ⁇ er what is currently available.
  • the versatility of the treatment options, for example, modifying the dose and deliver)' at will, is unique
  • the health care provider can be more responsive to the patient feedback or changing clinical manifestations.
  • Therapeutic agents can be delivered singly, in combination, in series, or simultaneously.
  • One or multiple disc levels may be Heated at the same lime, with cervical, thoracic, lumbar, or multiple areas being targeted
  • Therapeutic agents may be applied interdiscally, adjacent to the disc, or intramuscularly.
  • Therapeutic agents may be directed to inhibit the effects of TNF- ⁇ , cyclooxygenase 2, prostaglandin E2, mediators of inflammation such as glutamate, kinins such as bradykinin, and substance P, for example, as previously described.
  • the invention is useful in the prevention and treatment of osteoporosis, osteoarthritis and rheumatoid arthritis.
  • rheumatoid arthritis particularly, is known to have an inflammatory origin, and therapeutic agents, such as inhibitors of the action of TNF - ⁇ , can be useful for allev iating pain associated with these conditions, particularly when delivered by the implant and method of the present invention
  • Peri prosthetic osteolysis is a major complication following total joint replacement.
  • Articulating prosthetic joint surfaces and polymethylmethacrylate (PMMA) cement may generate wear particles that cause a chronic inflammatory response and osteoclastic bone resorption (wear debris-induced osteolysis), resulting in mechanical failure of the implant TNF and IL-] have been shown to mediate wear debris-induced, or wear particle-induced.
  • osteolysis Controlled and directed delivery of TNF inhibitors according to the controlled administration system and method of the present invention at an implant site provides a method for preventing implant-associated osteolysis Osteolysis generally, whether wear- induced or caused by other factors, because it often occurs at individual sites such as sites of joint replacement surgery, is an appropriate target for therapy using the controlled administration systems and methods of the invention.
  • TNF ⁇ has been found to induce osteoclast-Hke ceils and the osteoclast is the cell that resorbs bone
  • sustained and directed (localized) administration of TNF- ⁇ inhibitors particularly if combined with administration of osteoinductive factors such as BMP, GDF. LMP. or a combination of both, for example, can provide both pain relief and inhibition of bone resorption.
  • the method and system of the invention provides a means for alleviating such pain and making a cancer patient more comfortable, as well as inhibiting bone resorption or stimulating bone growth at the site.
  • the method of the invention can be provided by a targeted delivery system comprising an interbody or similar pharmaceutical pump, an optional catheter fluid ⁇ y connected to the pump to provide a channel for at least one pharmaceutical composition to be transported from the pump to a target site, and a therapeutic quantity of at bast one therapeutic agent such as, for example, a TNF inhibitor.
  • a targeted delivery system comprising an interbody or similar pharmaceutical pump, an optional catheter fluid ⁇ y connected to the pump to provide a channel for at least one pharmaceutical composition to be transported from the pump to a target site, and a therapeutic quantity of at bast one therapeutic agent such as, for example, a TNF inhibitor.
  • such a system may also comprise at least one modified release pharmaceutical carrier for the at least one therapeutic agent.
  • a depot can comprise at least one modified release pharmaceutical carrier for at least one therapeutic agent, and a therapeutically effective amount of at least one therapeutic agent, such as, for example, a TNF inhibitor
  • a therapeutically effective amount of at least one therapeutic agent such as, for example, a TNF inhibitor
  • kits comprising at least one depot provided in sterile packaging and at least one aliquot of at least one therapeutic agent in a package so that the therapeutic agent is provided in sterile form when introduced into the body.
  • kits can also comprise at least one package containing at least one aliquot of at least one therapeutic agent in combination with one or more r ⁇ odified-reiease pharmaceutical carriers.
  • Kits can also provide modified-release carriers containing a therapeutic agent within them, the modi fied-iei ease carriers being enclosed or partially enclosed within a matrix or containment device for complete or partial containment of the modified-reiease carriers, the matrix or containment device being provided in sterile packaging and being appropriate for implantation into a target site within the body of a subject in need of therapy utilizing the at least one therapeutic agent.
  • a therapeutically effective amount of an anti-inflammatory agent is administered to a patient in need of said treatment
  • the antiinflammatory agent is selected from the group consisting of TNF, IL-!, IL-6, IL-8, IL- 12, IL-15, IL- 17, IL- 18, GM-CSF, M-CSF, MCP- !
  • tumor necrosis factor alpha refers to a human TNF- ⁇ molecule comprising the amino acid sequence as described in P ⁇ nnica et al. Nature, 312.721 (1984) or Aggarwal et al , JBC, 260 2345 (1985).
  • human TNF- ⁇ ⁇ abbreviated herein as hTNF ⁇ , or simply hTNF
  • hTNF ⁇ a human cytokine that exists as a J 7 kD secreted form and a 26 kD membrane associated form, the biologically active form of which is composed of a trimer of nonco ⁇ aJently bound 17 kD molecules.
  • hTNF ⁇ The structure of hTNF ⁇ is described further in. for example, Peunica, D.. et al (1984) Nature 312.724-729, Davis, J M , et al ( ⁇ >87) Biochemistry 26 1322- ! 326, and Jones, E, Y , et al. ⁇ 1989) Nature 338:225-228.
  • human hTNF ⁇ is intended to include recombinant human rhTNF ⁇ , which can be prepared by standard recombinant expression methods or purchased commercially (R & D Systems, Catalog No 210-TA. Minneapolis, MN) hTNF ⁇ is also referred to as TNF.
  • TNF ⁇ inhibitor includes agents which interfere with a biological function of TNF- ⁇ , generally through binding to TNF- ⁇ and neutralizing its activity. Examples of
  • TNF- ⁇ inhibitors include etanercept (Enbrd ⁇ Arnge ⁇ ), infliximab (Remicade*, Johnson and Johnson), human anti-TNF monoclonal antibody Adalimumab(D2E7/HUMlRA ⁇ Abbott Laboratories), CDP 571 (Celltech), and CDP 870 (Celltech), as we! J as other compounds which inhibit TNF- ⁇ activity, such that when administered to a subject suffering from or at risk of suffering from a disorder in which TNF- ⁇ activity is detrimental, the disorder is treated
  • the term also includes each of the a ⁇ ti-TNF- ⁇ human antibodies and antibody portions described in U.S. Pat Nos 6,090,382; 6,258,562, 6,509,015. and in U S patent application Ser. Nos. 00/801. 185 and 10/302,356, each incorporated by reference herein.
  • the osteoinductive compositions or factors, used in this. invention as therapeutic agents further comprise a therapeutically effective amount to stimulate or induce bone growth of a substantially pure bone inductive or growth factor or protein in a pharmaceutically acceptable carrier.
  • the preferred osteoinductive factors are the recombinant human bone raorphogenetic proteins (rhBMPs), because they are available in relatively unlimited supply and do not transmit infectious diseases.
  • the bone morphogenetic protein is a rhBMP-2, rhBMP-7 or heterodimers thereof.
  • any bone morphogeiietic protein is contemplated, including bone morphogenetic proteins designated as BMP-I through BMP-13. BMPs are available from Genetics Institute, Inc., Cambridge, Mass.
  • Osteoinductive factors included within the scope of the present invention are BMP-I .
  • osteoinductive factors are contemplated whether obtained as above or isolated from bone. Methods for isolating bone morphogenetic protein from bone are described in U S Pat No. 4,294,753 to urist and Urist et a! , Sl PNAS 371 , 1984.
  • Recombinant BMP-2 can be used at a concentration of about 0.4 mg.'ral to about 2.5 mg/ml, preferably near about 1.5 rag/ml
  • any bone morphogenetic protein is contemplated, including bone morphogenetic proteins designated as BMP- I through BMP-] 8
  • the bone growth inductive factor may be supplied as a therapeutic agent for a drug depot implant of the present invention in any suitable manner.
  • the osteogenic factor preferably BMP
  • the osteogenic factor may be provided in freeze-d ⁇ ed form or in any other suitable liquid or gel carrier.
  • Any suitable medium or carrier capable of delivering the proteins to the implant is contemplated.
  • the medium is supplemented with a buffer solution, as is. known in the an.
  • synovial joint refers to a moveable articulation of two or more bones
  • the articulation is defined by a synovial cavity, which contains a volume of synovial fluid, is lined with a synovial membrane, and is surrounded by a fibrous capsule.
  • the opposing bone surfaces are each covered with a layer of cartilage
  • the cartilage and synovial fluid reduce friction between the articulating bone surfaces and enable smooth movements.
  • Synovial joints can be further distinguished by their shape, which controls the movements they allow. For example, hinge joints act like the hinge on a door, allowing flexion and extension in just one plane An example is the elbow between the humerus and the ulna.
  • Ball and socket joints such as the hip, allow movement in several planes simultaneously Condyloid (or ellipsoid) joints, such as the knee, permit motion in more than one plane in some positions but not others. For example, no rotation is possible in the extended knee, but some rotation is possible when the knee is flexed Pivot joints, such as the elbow
  • Synovial joints include, but are not limited to, shoulder (glenohumeral and acromioclavicular), elbow (ulno-humerai, radio-capitellar and proximal radioulnar), forearm (radioulnar, radiocarpal, ulnocarpal), wrist (distal radioulnar, radio-carpal, ul no- carpal, mid carpal), hand (carpo-nietacarpal, metacarpophalangeal, interphalangeal), spine (intervertebral), hip.
  • knee, ankle Uibiotaiar, tibiofibular), and foot talocaicaneai, talonavicular, intertarsal, tarso-meratarsal, metatarsal-phalangeal, interphalangeai).
  • implants may be formed from hydrophilic materials, such as hydrogels. or may be formed from biocompatible etastomeric materials known in the art, including silicone, polyurethane, polyolefins such as polyisobutylene and polyisoprene. copolymers of silicone and polyurethane, neoprene, nitrile. vulcanized rubber and combinations thereof.
  • the vulcanized rubber is produced by a vulcanization process utilizing a copolymer produced, for example, as in U.S. Pat. No. 5,245,098 to Summers et a!., from 1-hexene and 5-methyl-1.4-hexadiene.
  • hydrophilic materials are hydrogels.
  • Suitable hydrogels include natural hydrogels, and those formed from poi) vinyl alcohoi, aciylamides such as polyacrylic acid and poly (acrylommatie-acrylic acid).
  • py ⁇ olidone a ⁇ ylates such as ethyl methaciyiate
  • copohmeis of acrj lates with N-vim ! pj ro ⁇ done lactams. acry!amide
  • polyurethanes and polyacrylonitrile may be foimed from other similar materials that foim a hydrogel
  • the hydrogels include natural hydrogels, and those formed from poi) vinyl alcohoi, aciylamides such as polyacrylic acid and poly (acrylommatie-acrylic acid).
  • py ⁇ olidone a ⁇ ylates such as ethyl methaciyiate
  • In drogel materials may further be cross-linked to provide further strength Io the implant
  • poiyurethan.es include thermoplastic or thermoset pohurethanes, aliphatic or aromatic poWurethanes. poi ⁇ etherurethane, poKcarhonate- urethane and silicone pol ⁇ ether-urethane
  • suitable hvdrophilic polymers include naturally-occurring materials such as glucomannan gel hyaluronic acid, polysaccharides, such as cross-linked l-containing pol> saccharides, and combinations theieof
  • the implants of the invention ma> be made of at least in part of a biocompatible material
  • the implants r ⁇ a> be made of an implantable material, such as a material suitable for implantation in bone, implantation in cartilage, and/or implantation in other hiornaterials in a joint
  • the implant may be formed at least in part of a material that can maintain its integrity during implantation This may help prevent leakage of a drug in the carriei through a crack or fissure in the implant
  • the implant reservoir may be constructed Horn a metal, such as titanium, nickel titanium, stainless steel, anodi/ed aluminum, oi tantalum, or a plastic, such as lene, nylon, or poWurethane
  • the implant may also include a material oi modified material to allow for osseous mtcgiation of the implant, i e , bone ingrowth
  • suitable materials will be apparent to one of ordinary skill in the art Moreover, combinations of materials may be used
  • T he implants of the imention may be provided with surface features defined in their outer surfaces
  • a projection may be formed on the end w alls instead of a slot
  • Such a projection may form a straight, flat-sided shape, an elliptical eminence, a biconcave eminence, a square eminence, ot am othei piotiuding shape which provides sufficient end-cap or tool-engaging end strength and drive purchase to allow transmission of insertionai torque without breaking or otherwise damaging the eminence
  • Yet other surface features can be defined on the implant
  • the outer surface of the implant may define barbs or other surface features that may stabilize the diug depot implant interface with tissue and reduce micromotion
  • the drug depot implants of the present invention may be designed for placement and location within or near the synovial joint, spina! disc space, spinal canal or the surrounding soft tissue. In some embodiments, the contemplated placement and location areas of the drug depot implants within the desired location of the subject will not cause damage to the bone
  • placement of the device in a patient may be an intraarticular region of a synovial joint where there is no interfacing articular cartilage. It may be located, for example, within the inside of the knee capsule that is non-load-bearing and removed from the articulation surface of the synovial joint
  • the device may be attached within the synovial joint, allowing for continuous exposure to syno ⁇ iai fluid flow and resulting release of anti-inflammatory or osteogenic therapeutic agents, without damaging the articular surface that is in apposition during range of motion of the given joint
  • the therapeutic agent e.g., an ti -inflammatory agent or osteoinductive factor
  • the gas-filled lipid-containing microspheres may further comprise biocompatible polymers on their outer surfaces
  • the present invention provides that the therapeutic agent may also be contained in a freeze dried state within the microsphere to preserve its stability and activity over an extended period of time. Si mil ar!y. the present invention also provides that the therapeutic agent may be contained in a freeze dried state within the depots to preserve it ' s stability and activity over an extended period of time.
  • Non-limiting examples of suitable gases are air, nitrogen, carbon dioxide, oxygen, argon, fluorine, xenon, neon, helium, or any and all combinations thereof
  • fl ⁇ orinated gaseous compounds such as various perfluorocarbon, hydrofiuorocarbo ⁇ , and sulfur hexafiuoride gases may be utilized in the preparation of the gas filled microspheres.
  • lipid materials for the biocompatible lipid materials, it is preferred that such lipid materials be what is often referred to as "amphophilic" in nature (i.e . polar lipid), by which is meant any composition of matter which has, on the one hand, lipophilic, i.e , hydrophobic properties, while on the other hand, and at the same time, having hydrophilic properties
  • the lipid may alternatively be in the form of a monolayer, and the monolayer lipids may be used to form a single monolayer (unilamellar) arrangement.
  • the monolayer lipid may be used Io form a series of concentric monolayers, i e , oligoiamellar or multilamellar, and such arrangements are also considered to be within the scope of the i nvention
  • Non-limiting examples of suitable lipids are fatty acids, iysolipids, phosphatidylcholine with both saturated and unsaturated lipids, dimyristoylphosphatidylchoUne, dipentadecanoyiphosphatidy ⁇ choiine.
  • d auroy 1 phosphatidy lchol ine, di patmitoy 1 phosphat i dy 1 chol i ne (DPPC ), distearoySphosphatidyleholine (DSPC).
  • phosphatidylethanolamines phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, sphingolipidsglycolipids, gl ⁇ colipids.
  • sulfatides glycosphingolipids, phosphatidic acids, palmitic acid, stearic acid, arachidonic acid, oleic acid, lipids bearing polymers, lipids bearing sulfonated mono-, di-, oligo- or polysaccharides, cholesterol, cholesterol sulfate and cholesterol hemi succinate, tocopherol hemisuccinat ⁇ .
  • lipids with ether and ester-linked fatty acids polymerized lipids, diacetyl phosphate, dicetyl phosphate, stearylamine, cardioiipin, phospholipids with short chain fatty acids of 6-8 carbons in length, synthetic phospholipids with asymmetric acyl chains
  • ceramides e.g , with one acyl chairs of 6 carbons and another acyl chain of 12 carbons
  • ceramides non-ionic liposomes
  • polyoxyethyle ⁇ e fatty alcohols polyoxyethylene fatty alcohol ethers
  • polyoxyethylated sorbitan fatty acid esters polyoxyethylated sorbitan fatty acid esters
  • glycerol polyethylene glycol oxystearate e.g , with one acyl chairs of 6 carbons and another acyl chain of 12 carbons
  • glycerol polyethylene glycol ricinoleate eth ⁇ xylaied soybean sterols, ethoxylated castor oil, polyoxyethylene-polyoxypropyiene polymers, and polyoxyethylene fatty acid stearates
  • sterol aliphatic acid esters including cholesterol sulfate, cholesterol b ⁇ tyrate, cholesterol iso-butyrate, cholesterol paimitate, cholesterol stearate.
  • lanosterol acetate, ergosterol paimitate, and phytosteroi n-butyrate sterol esters of sugar acids, esters of sugar acids and alcohols, esters of sugars and aliphatic acids, saponins, glycerol dilaurate, glycerol trilaurate, glycerol dipalmitate, glycerol and glycerol esters, longchain alcohols, djgalactosyldiglyceride, 6 ⁇ 5-cholesten ⁇ 3 beta -ylo ⁇ y)hexyS-o-anuno ⁇ 6-deoxy-1 -thio- .beta.-D-gaiacto pyranos ⁇ de, 6-(5-choiesten-3 beta -yJoxv)hexyl-6-amino-c>-deoxyl-l-thio- alpha -D-manno pyranoside, 12-(((7'-diethy ] amino
  • Polymers suitable for this embodiment of the present invention can be natural, semi- synthetic or synthetic.
  • Exemplary natural polymers suitable for use in the present invention include naturally occurring polysaccharides, such as for example, ambinans, fructans, fucans, galactans, galacturonans. glueans, mannans, xylans (such as, for example.
  • inulin leva ⁇ , fueoidars, carrageenan, gaiatocarolose, pectic acid, pectin, amylose, pull ⁇ lan, glycogen, ainylopec ⁇ n, cellulose, dextran, pustulan, chi ⁇ n, agarose, keratao, chondroitan, dermatan, hyaluronic acid, alginic acid, xa ⁇ than gum, starch and various other natural homopolymer or heteropolyrnerx such as those containing one or more of the following aldoses, ketoses, acids or amines: erythrose, threose, ribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose, g ⁇ lose, idose, galactose, talose, erythmlose, r ⁇ bulose, xylulose, ps ⁇ cose, fructose, sorbos
  • Exemplary semi-synthetic polymers include carboxymethylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, methylcelluloae, and raetlioxycellulose.
  • Exemplary synthetic polymers suitable for use in the present invention include polyethyien.es (such as, for example, polyethylene glycol, polyoxyetliylene, and polyethylene ierephthiaie), poly propylenes (such as, for example, polypropylene glycol), polyurethanes (such as, for example, polyvinyl alcohol (PVA), polyvinylchloride and polyvinylpyrrolidone), polyamides including nylon, polystyrene, poiylactic acids, fluorinated hydrocarbons, fluorinated carbons (such as, for example, polytetrafiuoroethyleneX and polymethylmethacrylate, and derivatives thereof.
  • PVA polyvinyl alcohol
  • PVC polyvinylchloride
  • the gas-filled lipid-containing microspheres of the present embodiment can be prepared, for example, by shaking an aqueous solution comprising a lipid in the presence of a gas at a temperature below the gel state to liquid crystalline state phase transition temperature of the lipid.
  • the shaking must be of sufficient force to result in the formation of microspheres, particularity stabilized microspheres.
  • the shaking may be by swirling. such as by vortexing, side-to-side, or up-and-down motion. Different types of motion may be combined.
  • the shaking may occur by shaking the container holding the aqueous lipid solution, or by shaking the aqueous solution within the container without shaking the container itself.
  • the motion be reciprocating in the form of an arc between about 2 degrees and about 20 degrees, more preferably, about 6 5 degrees. It is contemplated that both the arc and the rate of reciprocation are critical to determining the amount and size of the gas and gaseous precursor filled microspheres formed. It is a preferred embodiment of the present invention that the number of reciprocations, i.e . fuM cycle oscillations, be within the range of about 1000 to about 20,000 per minute.
  • the gas and gaseous precursor filled microspheres made by the method described above can then be sized by optical microscopy. It should be determined that the largest size of the microspheres ranges from about 50 to about 60 m and the smallest size detected should be about S . m The average size should range from about 15 to about 20 m
  • the gas and gaseous precursor tilled microspheres may then be filtered through an 8, 10 or 12 ni "NUCLEPORE” membrane using a Swin-Lok Filter Holder, ( " Nuclepore Filtration Products, Oostar Corp., Cambridge, Mass.) and a 20 cc syringe (Becton Dickinson &. Co , Rutherford, NJ.). The membrane may be a 10 or 12 . "m "NUCLEPORE” membrane (Nuclepore Filtration Products, Costar Corp., Cambridge,
  • the 10.0 m filter is> placed in the Swin-Lok Filter Holder and the cap tightened down securely.
  • the lipid-hased microsphere solution is shaken up and it is transferred to the 20 cc syringe via an IS gauge needle Approximately 12 ml of gas-filled foam solution may be placed in the syringe, and the syringe screwed onto the Swin-Lok Filter Holder.
  • the syringe and the filter holder assembly are inverted so that the larger of the gas and gaseous precursor filled microspheres can rise to the top. Then, the syringe is gently pushed up and the gas and gaseous precursor filled microspheres are filtered in this manner.
  • the survival rate (the amount of the gas and gaseous precursor filled microspheres that are retained after the extrusion process) of the gas and gaseous precursor filled microspheres after the extrusion through the 10.0 . m filter is about 83-92%
  • the volume of foam is about 12 ml and the volume of aqueous solution is about 4 ml.
  • the volume of foam ia about 10-S l mi and the volume of aqueous solution is about 4 mi
  • the optica! microscope may be used again to determine the si/.e distribution of the extruded gas and gaseous precursor filled microspheres, ⁇ t is determined that the largest size of the microspheres ranges from about 25 to about 30 m and the smallest size detected is about 5 m. The average size ranges from about 8 to about 15 m.
  • the present invention contemplates drag depot implants as depicted in FlG. 1.
  • FlG. 1 is a cross-sectional view of a rod-shaped drug depot implant 10 comprising one or more small barbs 12 that serve as anchoring devices to minimize migration of the implant in a patient ' s tissue once implanted
  • the term "rod-shaped" is intended Io indicate any shape with a longitudinal axis, i e.. is longer along one direction than in other directions, the cross- sectional shape across the longitudinal axis may be any shape, but is preferably elliptical or circular
  • the rod-shaped implant ' s length can range from about 1 mm to about 10 cm; its diameter can range from about 0 5 mm to about 5 cm.
  • a preferable length may be from about 2 cm to about 10 cm with a preferable diameter ranging from about 1 mm to about 2 mm
  • Alternative preferable length can range from about 2 cm to about 10 cm; with an alternative preferable diameter ranging from about 2 mm to about 1 cm.
  • the implant 10 comprises a rod-shaped ⁇ or bullet-shaped) body 14 that is made from a biodegradable material.
  • the body may be made from a non-biodegradable material.
  • a nonbiodegradable body could be a porous hollow chamber filled with the therapeutic agent alone or incorporated into a degradable polymer.
  • the body 14 may be desirable to make the body non-degradable to be able to retrieve it after it has released its contents
  • the non- biodegradable body could be a small pump that pushes the contents out pores, port(s), or a cannula
  • suitable biodegradable materials for the body 14 include polyorthoesters (POE), polylactkglycolic acid (PLGA) polysac c harides (Saber technology), polycapralactone, polyfemarate, tyrosine polycarbonate, etc
  • the body 14 is solid, and a therapeutic agent 16 ia dispersed throughout the material that forms the body 14.
  • the dispersal of the therapeutic agent 16 may be even throughout the body i4 Alternatively, the concentration ⁇ f die therapeutic agent 16 may vary as a function of the distance from the longitudinal centerline 18 of the body 14, or as a function of a distance along the longitudinal centerline IS. As the biodegradable material of the body 14 degrades within the tissue, the therapeutic agent 16 is released. Suitable sustained release materials may be used for the body 14 to carry the one or more therapeutic agents 16 and control the release of the therapeutic agent(s) 16 For example, microspheres may be used to encapsulate the therapeutic agent; the therapeutic agent-containing microspheres are then dispersed through the body 14 The one or more barbs 12 serve as an anchoring system and are designed to permit forward translati ona!
  • the barbs 12 extend from the body 14 and point backwards along the longitudinal axis 18.
  • the barbs 12 may be made from the same material from which the body 14 is made, or from a different material.
  • the barbs 12 may be made from a secondary material that degrades more slowly than the primary material of the body 14, and attach to a core of such secondary materia! that runs through the longitudinal centerline 18 of the body 14
  • the present invention provides other designs for gradient variations in biodegiadafoilUiy to hold the depot in place while the secondary material releases it ' s contents.
  • the baits could be a "snap-on" component that tits over the depot containing the therapeutic agent
  • the manufacturing of the drug loaded depot is made easier instead of having to injection mold the barbs into the depot.
  • the barbs 12 may be axially aligned or circumferential] ⁇ ' spaced in relation to each other about the daig depot implant 10.
  • the implant 10 may be designed to be affixable within a joint.
  • the implant 10 may have a width from about 1 mm to about 6 mm and a length from about 5 mm to about 20 mm Selection of suitable lengths and widths for the device 10 will depend upon the targeted implant site, and is well within the abilities of those having ordinary skill in the art.
  • FiG, l is a cross- sectional view of another implant 20
  • the implant 20 comprises one or more barbs 22 that permit forward motion of the implant 20 while retarding backward motion, thus serving as an anchoring system to anchor the implant 20 within the targeted deliver)' site.
  • the implant 20 comprises a rod- shaped shell 24 that is made from a non-biodegradable material, such as polyethylene. delrin, polyurethane.
  • the shell 24 may be made from a biodegradable material that degrades relatively slowly within the implant site.
  • Suitable biodegradable materials include POE 5 PLGA, PLA, PGA 5 and all the oilier standard degiadable polymers
  • the shell 24 forms a cavity 25, and one or more therapeutic agents 26 are disposed within the cavity 25,
  • the therapeutic agents 26 may be, for example, in freeze- dried form, dispersed in a carrier, contained within microspheres, or packed in any other suitable manner within the cavity 25
  • the shell 24 is permeable to the therapeutic agent 26 5 however packed, so that the therapeutic agent 26 can diffuse through the shell 24 and into the surrounding tissue.
  • the shell 24 may comprise a plurality of pores through which the microspheres may pass to subsequently release the therapeutic agent in or near the targeted tissue.
  • the microspheres may release the therapeutic agent within the shell 24, and then the therapeutic agent may diffuse through the shell 24 to the targeted tissue through pores or be hydrolocally pumped out of the device.
  • the diffusion rate of the therapeutic agent 26 may be controlled by the thickness of the shell 24. by the number and diameter of the pores within the shell 24, or by the concentration of the therapeutic agent or the medium (gelatin. POE, PLGA. etc ) in which the therapeutic agent is embedded
  • the barbs 22 may be made from the same material as the shell 24 and may be disposed in any suitable maunei about the ouiei surface of the shell 24. If the shell 24 is made from a biodegradable material, the type and thickness of the material used should be sufficient to ensure that all, or nearly all, of the therapeutic agent 26 has dispersed into the surrounding tissue before the integrity of shell 24 is substantially compromised.
  • FIG. 3 is a side view of another implant 30.
  • the implant 30 may be solid, as in the implant 10, or shell-like, as in the implant 20.
  • the implant 30 has a rod-shaped outer surface 34 from which a therapeutic agent, contained internally of the outer surface 34, diffuses, as discussed above. Extending from the outer surface 34 are one or more first barbs 32 and one or more second barbs 36.
  • the first barbs 32 point backwards along the longitudinal axis 38 to prevent backward movement of the implant 30 (i e., movement opposite to the direction indicated by longitudinal centerline arrow 38);
  • the second barbs 36 point forwards along the longitudinal axis 38 to prevent forward movement of the implant 30 (i.e , movement along the longitudinal centerline arrow 3S).
  • the baits 32, 36 thus serve as an anchoring system to keep the implant 30 at the targeted delivery site, that is, the anchoring systems prevent both forward and backward lranslational movement of the implant 30
  • the barbs 12, 22. 32, 36 in the above examples may be flexible, that is, they may be compressible towards the centerline of the longitudinal axis 18, 28. 38 This may assist in the targeted delivery of the implant 10, 20, 30.
  • a targeted delivery system 41 which may be a catheter, a syringe, or any other suitable de ⁇ ice
  • the targeted delivery system 41 may include a cannula 43 in which, the implant 40 is disposed.
  • the implant 40 has flexible barbs 42 that extent as they exit from the cannula Ai.
  • FIG. 5 is a side view of another embodiment implant 50.
  • the implant 50 has a rod-shaped outer surface 54 from which elutes a therapeutic, agent contained therein. Extending from the outer surface 54 is one or more extensions 52 adapted to prevent both forward and backward transSational movement of the implant 50, and which thus serve as an anchoring system to keep the implant 50 at the targeted delivery site
  • the extensions 52 may be flexible, and hence may extend once released from a targeted delivery device.
  • the extensions 52 point substantially 90 degrees away from the longitudinal axis 58.
  • the anchoring system provided by the extensions 52 may also prevent rotational movement of the implant 50
  • Implants of the present invention may contain radiographic markers, that assist in the imaging of the implants, and hence in the targeted delivery of the implants.
  • the radiographic markers may be made from any suitable material, as previously discussed, and may be, for example, ring-shaped or dispersed as small peilets throughout the implant
  • An implant 60 utilizing ring-shaped radiographic markers is depicted in FIG. 6
  • one or more radiographicalSy active rings 62 are positioned in or on the body 64 of the implant 60. Each ring 62 is placed at a predetermined position within the body 64, and thus when imaged enables a physician to determine the position and orientation of the implant 60.
  • FlG 7 presents another possible embodiment for radiographic markers as applied to an implant of the present invention.
  • An implant 70 comprises a body portion 74 that holds and elutes the therapeutic agent. Regularly dispersed throughout, or on, the body portion 74 are small beads 72 of a radiographically active substance. Imaging of the beads 72 provides a clear indication of the position and orientation of the body portion 74 within the target tissue. Alternatively, the beads 72 may be disposed in or on the body portion 74 according to a predetermined pattern; imaging of this pattern presented by the beads 72 will similarly provide solid reference for the position and orientation of the body portion 74,
  • FlG. 8 is a side view of another implant 80.
  • the implant 80 has a rod-shaped body portion 84, which may be tapered, from which extends a first anchoring system 82 and a second anchoring system 86 that secure the implant 80 within the targeted tissue location.
  • the first anchoring system 82 is configured as one or more barbs 82, which point backwards with respect to the forward (or insertion) direction indicated by longitudinal centerline arrow 88 The barbs 82 thus prevent the implant 80 from backing out of the implant site.
  • the barbs 82 may be flexible
  • the second anchoring system 86 is an end cap 86 that is adapted to abut against a tissue plane. A forward surface 89 of the en ⁇ cap
  • Both the barbs 82 and the end cap 86 may be made from the same material as the body potion 84
  • the body portion 84 may be hollow or solid and may or may not be biodegradable, as described previously.
  • the body portion S4 contains and elutes the desired therapeutic agent Although the therapeutic agent may be dispersed throughout the body portion 84 as well as throughout the barbs 82 and end cap 86, it may be desirable to dispose the therapeutic agent only within a forward region of the body portion 84. For example, it may be desirable to dispose the therapeutic agent only within the forward two-thirds of the body portion 84, as indicated by arrow 8 ! .
  • the therapeutic agent in only the forward half of the body portion, as indicated by arrow 83, or only the forward third, as indicated by arrow 85. Indeed, it may be desirable to have the therapeutic agent disposed only within a tip region 87 of the body portion 84. Hence, depending upon the region 81, 83, 85, 87 selected, the therapeutic agent will only eiute from that specific region 81. 83, 85, 87 of the implant 80.
  • the forward end 81, 83, 85. 87 of the body portion 84 that contains the therapeutic agent may be termed the active end of the implant 80.
  • the end cap 86 may be formed with the body portion 84, Le , be monolithic with the body portion 84, or may be provided as a separate element. If provided as a separate element, the end cap 86 and body portion 84 should have corresponding mating elements that enable a physician to attach the end cap 86 to the body portion 84 after the body portion 84 has been deployed at a targeted tissue site Any suitable mating system may be used such as for example, mechanical snap-on or threaded fixation. As shown in FfG 9, an implant 90 of the instant invention may be disposed in a disc 91 to alleviate diskogenic pain A disc 91 to be treated is sandwiched between two vertebrae 93 The implant 90 is.
  • the implant 90 has an anchoring system 02 that extends from the impiant Q G to keep the implant 90 firmly constrained to the targeted tissue site, preventing forward and backwards movement of the implant 90 within the disc 9 ! ,
  • the implant 90 also has an active region 94 that elutes a therapeutic agent 96 into the disc 91.
  • the concentration gradient of the eluted therapeutic agent 96 may extend from 1 cm to as far as S cm from the active region 94 of the implant 90.
  • the implant 80 of FIG. 8 is shown deployed in the synovial cavity 102 of a synovial joint 100 in FlG 10
  • the joint 100 depicted is an idealized synovial joint but roughly approximates the femur-tibia articulation at the knee.
  • Exemplar ⁇ ' placement of the impiant SO is indicated
  • the placement of the implant 80 is in the joint and is remote from the bone.
  • the forward surface 89 of the end cap 86 abuts against the synovial membrane 104, thus preventing forward movement of the implant 80 into the joint 100.
  • the barbs 82 prevent the implant 80 from backing out of the joint 100.
  • An active end 106 of the implant 80 elutes a therapeutic agent 108 into the synovial fluid of the cavity 102.
  • FIG. 1 1 is a side view of another implant 110.
  • the implant 110 comprises a tapered, rod-shaped body portion 1 14 and a suture 1 12 that extends from the body 1 14
  • the body 1 14 may be hollow or solid, as previously described, and may be made from a biodegradable or non -biodegradable material
  • the body 1 14 contains, and elutes, a therapeutic agent.
  • the entire body 1 14 may be active (i.e., elute the therapeutic agent), or instead may have an active region in a predetermined position, as indicated earlier for other embodiments.
  • the suture 1 12 may be made from a biodegradable or nonbiodegradable material.
  • the suture ⁇ 12 enters from a central region 116 of the body 114, substantially circumnavigates the body 1 14, and then exits from the central region 1 16.
  • the suture 1 12, extending from the body portion 1 14, serves as an anchoring system for the implant 1 10.
  • FlG 12 shows another implant 120 that similar!) utilizes a suture 122
  • the suture 122 may traverse just under the body portion 124 In the implant 120. however, the suture 122 enters the body portion 124 from a first end region 126 of the bod ⁇ 124 and exits.
  • the end legions 126, 128 ma> include, for example, the outer third of the body portion 124. with respect to the longitudinal axis 129
  • FIG 13 Another embodiment implant 130 is shown in FIG 13
  • the suture 132 enters at or near a first cndpoint 136 of the body 134, traverses within the body
  • the cndpoints 136, 138 are defined by the longitudinal centerline 139 of the body 134
  • FIG 14 shows, for example, deployment of the implant 1 10 of FIG 1 1 in a synovial joint 140
  • the bullet-shaped tip of the body 1 14 eases insertion of the implant 1 10 through the joint capsule tissue 142 and minimizes tissue disH ⁇ tion
  • a very small hole is made in the joint capsule 142 with a blunt piobe, and then the tapered rod i 14 is slo ⁇ i ⁇ pushed through this hole, slow l ⁇ stretching the tissues apart to minimize tissue tearing
  • the hole in the joint capsule 142 closes upon itself
  • the suture 1 12 embedded in the rod 1 14 is left passing through the capsule 142 so that it can be pulled taut and knotted up against the outside of the joint capsule 142, forcing the depot 1 K* up against the inside of the joint capsule
  • HG 15 shows the implant 120 of FlG 12 deplo ⁇ ed in a syno ⁇ ial joint 150
  • the suture 122 exits from two points in the joint capsule 152
  • the ends of the suture 122 may be tied off together or separately This design offers the advantage of holding the depot J 20 up against the inside of the joint capsule ⁇ 52 without rotating and potential!) interfering with motion of the joints 150
  • the beads 164 may be in the form of a solid, biodegradable material, such as a polymer, loaded wiih a therapeutic agent, alternatively, the beads 164 may form a cavity that is packed with the therapeutic agent, and which may diffuse through the walls of the cavity. The beads 164 elute the therapeutic agent when disposed within the targeted tissue site.
  • the beads 164 may be from about 100 ⁇ m to about 5 mm in diameter, it may be more preferable that the beads !64 range in size from about I mm to about 2 mm.
  • the suture 162 may be either a degradable or a non-degradable material. Extending from an end of the implant 160 is an optional needle or barb 166 to serve as an anchoring device that retains the strand 160 within the targeted tissue site, such as a disc or joint capsule.
  • This implant 160 optimally positions the therapeutic agent eluting beads 164 along the route of inflamed tissue, resulting in a more effective distribution of the therapeutic agent and clinical effectiveness
  • the strand 160 may be implanted by inserting a cannula 170 containing the strand 160 of beads 164 as far as desired inside, for example, a disc, joint, or soft tissue, and then deploying the barb 166 into the soft tissue
  • FIGS. 18 and 19 illustrate the implant 160 being deployed in targeted tissue sites.
  • a very small hole is made in an intervertebral disc 180 or in a joint capsule 192 with a blunt probe, through which a cannula is inserted to implant the string 160 of beads 164.
  • the implant 160 may be deployed inside a disc 180, with the anchoring device 166 embedded within the annular f ⁇ rosus of the disc 180.
  • the beads 164 may extend inside the disc 180, and then externally along the nerve root 182. As shown in FlG. 19, the implant 160 may be deployed transverse across a joint 190. resulting in a more uniform distribution of the therapeutic agent within the synovial cav ity 194 of the joint 190, The suture 162 at the ends of the implant 160 may be tied off to the joint capsule 192 to anchor the implant 160 within the joint 190.
  • the present invention provides another method for administering a therapeutic agent to a targeted tissue site.
  • the targeted tissue site may be a spinal canal 200 or tissue surrounding the spinal canal 200, such as a disc 202 or a nerve root 204
  • the spinal cord 206 rims through the spinal canal 200, which is provided by the vertebrae 208.
  • microspheres 209 encapsulating the desired therapeutic agent may be formed hi a known manner. These microspheres 209 may then be deployed into the spina! canal 200, such as by injecting a carrier containing the microspheres 209 into the spinal canal 200. The microspheres 209 then eluie the therapeutic agent into the spina! canal 200.
  • the microspheres 209 may disperse to the surrounding tissue, such as the nerve root 204 or the disc 202 Alternatively, to provide therapeutic treatment primarily to the disc 202 alone, the therapeutic-containing microspheres 209 may be directly injected into the disc 202. As shown in FiG. 21, microspheres 219 loaded with a therapeutic agent may he injected into a synovial cavity 212 to treat a joint 210. A syringe or similar device may be used to deploy the microspheres 2 I 9 into the joint cavity 212.
  • Microspheres may disperse relatively quickly, depending upon the surrounding tissue type, and hence disperse the therapeutic agent In some situations, this may be desirable; in others, it may be more desirable to keep trie therapeutic agent tightly constrained to a well-defined target site.
  • the present invention contemplates the use of adherent gels to so constrain dispersal of the therapeutic agent. These gels may be deployed, for example, in a disc space, in a spinal canal, or in surrounding tissue, or in a joint space, such as a synovial cavity. In this embodiment the gel is an adherent and/or settabie gel in order to stay in place within a joint space.
  • a depot comprises an adherent gel comprising a therapeutic agent that is evenly distributed throughout the gel.
  • the gel may be of any suitable type, as previously indicated, and should be sufficiently viscous as to prevent the gel from migrating from the targeted delivery site once deployed; the gel should, in effect, "stick " ' to the targeted tissue site.
  • the gel may, for example, solidify upon contact with the targeted tissue or after deployment from a targeted delivery- system.
  • the targeted delivery system may be, for example, a syringe, a catheter or any other suitable device.
  • the targeted delivery system may inject or spray the gel into or on the targeted tissue site.
  • the therapeutic agent may he mixed into the gel prior to the gel being deployed at the targeted tissue site.
  • the gel may be biodegradable.
  • non-settable gels they may be sold pre- mixed and just delivered, but for the adherent and/or settabie gel. they may need to be two component delivery systems that mix the two components upon injection to activate a chemical process to cause them to stick or set up
  • FIG. 22 illustrates a gel 212, imbued with a therapeutic agent and deployed around a targeted tissue site, a nerve root 210.
  • the gel 212 either viscous or solid once deployed, 40 keeps the therapeutic agent closely bound to the nerve root 210.
  • the present invention also contemplates dispersing microspheres within the gel, the microspheres loaded with the therapeutic agent
  • the microspheres provide for a sustained release of the therapeutic agent
  • the gel which is biodegradable, prevents the microspheres from releasing the therapeutic agent, the microspheres thus do not release the therapeutic agent until they have been released from the gel This embodiment is depicted in FlG 23.
  • the targeted tissue site Dispersed within the gel 222 are a plurality of microspheres 226 that encapsulate the desired therapeutic agent
  • Dashed line 227 indicates the original deployment region of the gel 222
  • solid line 225 indicates the current deployment region of the gel 222 due to degradation of the ge! 222.
  • Microspheres 226 are thus released from the gel 222. Certain of these microspheres 228 degrade once released from the gel 222, thus releasing the therapeutic agent.
  • a localized delivery device such as a pump or the like, may he used to deliver the microspheres to the targeted tissue site
  • a pump may be used to deliver the present invention gel, either with or without microspheres, to the target site.

Abstract

The present invention relates to novel drug depot implant designs for optimal delivery of therapeutic agents to subjects. The invention provides a method for alleviating pain associated with neuromuscular or skeletal injury or inflammation by targeted delivery of one or more therapeutic agents to inhibit the inflammatory response which ultimately causes acute or chronic pain. Controlled and directed delivery can be provided by drug depot implants, comprising therapeutic agents, specifically designed to deliver the therapeutic agent to the desired location by facilitating their implantation, minimizing their migration from the desired tissue location, and without disrupting normal joint and soft tissue movement.

Description

DRl'G DEPOT IMPLANT DESIGNS AND METHODS QF IMPLANTATION
FIELD OF THE INVENTION The present invention broadly concerns drug depot implant designs for optimal delivery of therapeutic agents to subjects. In specific applications of the invention the compositions include novel drug depot implant designs for optimal delivery of antiinflammatory agents and/or grow th factors to inhibit or eliminate the inflammatory response that may result in acute or chronic pain and further tissue damage after disease or injury
BACKGROUND OF THE INVENTION
Current approaches for treating pain and'or inflammation involve systemic delivery of therapeutic agents Anti-inflammatory agents target tumor necrosis factor alpha (TNF-α) which appears early in the inflammatory cascade following infection or injury It is produced by monocytes, macrophages, and T lymphocytes. TNF~σ exerts its primary' effects on monocytes, synovial macrophages, fibroblasts, chondrocytes, and endothelial ceils, and stimulates proinflammatory cytokine and chemokine synthesis. It activates granulocytes, and increases MHC Class 11 expression. It promotes secretion of matrix metalloproteinases (MMPs), leading to cartilage matrix degradation. Because it initiates an inflammatory cascade, and has been found to be increased in close proximity to inflamed or injured tissue, TNF-α inhibition is a target for pain therapy. Pro- TNF-α is expressed on the plasma membrane, then cleaved in the extracellular domain
Trimerization is required for biological acti\ ity, TNF-α acts through two receptors (TNFRs)' Type I receptors (pόO, p55, CO 120a) are expressed constitutive! y on most cell types and Type II receptors (p80, p75, CD 120b) are inducible. Popular TNF-α inhibitors act primarily to inhibit binding of TNF-u to its receptors. There are currently two major classes of TNF inhibitors 1 ) monoclonal antibodies to TNF-α. which prevent binding of TNF-α to its two cell-associated signaling receptors (p55 and ρ75) and 2) monomelic soluble forms of p55 or p75 TNFR dimerized by linking them to an immunoglobulin (Ig) Fc fragment. These lgs bind to TNF-α with high affinity and prevent it from binding to its cell -associated receptor.
TNF inhibitors have therefore been developed for therapeutic use for orthopedic and neuromuscular disease or injury that can cause pain, such as rheumatoid arthritis Cuiremly therapeutic agents are delivered systemically to treat bone- and caiu'lage- related defects related to degeneration, injury, infection, malignancy or de\ elopmenta! alfoiπiatiou TNF inhibitors currently in use aie gcncially administered sjsteinically via intravenous infusion and subcutaneous injection, but there are side effects of anti-FNF therapies associated with the higher doses and systemic administration that are common with these therapies A major disadvantage of these SΛ steim'c drug delivery systems, is thai the antiinflammatories are delivered in buffered solutions that have short half-lhes, therein requiring repeated administration to a patient, which can result in ad\erse effects due to the s\ stem of deli\ ery of relatk ely high doses of the drug Unfortunately, it provides a limited quantity of agent that must mo\ e through the tissue to the target site
This method is inadequate to seive the needs of patients Anti- J'NF therapy is generally needed over an extended period of time, so repeated injections are likely to be necessary In addition, injection site pain and reactions sometimes develop with anti- IT\F agents Recently, there have been a number of attempts to develop an acceptable implant and methods for treating disease in a patient
U S Patent Ko 6,203,813 discloses an opiate antagonist implant pellet for subcutaneous administration to a patient Aceoiding to the disclosure, the subcutaneous implant pellet releases the opiate antagonist in the patient to effectively inhibit the effects of a numbα of additive diugs to ueat dmg detoxification in a patient The subcutaneous implant is not substantial!) immobilized in the tissue of a patient but is free to mo\ e about under the skin Anothei drawback to this approach is that the delivery of the therapeutic agent is accomplished via the general s\ stemic circulatory s\ stem, the therapeutic agent is not delKered locally to the affected area
U S Patent No 6,735,475 discloses small implantable stimulators Wύh at least tuo electrodes that are small enough to hav e the electrodes located adjacent to a ner\ e structure at least paitialiy responsible for headache and/or facial pain 1 he implant works \ia electrical stimulation of a specified tissue and does not include a theiapeutic agent component as part of the dev ice, let alone involve deliver} of a therapeutic agent to desired tissue U S Patent No 6.735.475 describes a variety of implants for treating headache and/or facial pain, none of which arc suitable foi introducing therapeutic agents to a desired tissue of a patient U.S. Patent Application Publication No. 200400641*53 discloses an implant comprising collagen and/or other bioresorbable materials for deployment in select locations for regeneration of tissue According to the disclosure, the implant comprises a synthetic tissue substitute material and a method and system for deploying the implant. U.S. Patent Application Publication No. 20040064193 describes a variety of implants for regeneration of tissue, none of which are suitable for introducing therapeutic agents to a desired tissue of a patient.
U S Patent Application Publication No. 20050074481 discloses an implantable device comprising a poly electrolytic complex for facilitating the healing of voids in bone, cartilage and soft tissue. According to the disclosure, the implant provides m vivo cυhuring of tissue cells in a diverse tissue or homogeneous lesion U S Patent Application Publication No. 20050074481 describes a variety of implants for facilitating the healing of voids in bone, cartilage and soft tissue, none of which are suitable for introducing therapeutic agents to a desired tissue of a patient. V S Patent Application Publication No. 200501771 18 also discloses an implantable device comprising a polyelectrolytic complex for facilitating the healing of voids in bone, cartilage and soft tissue According to the disclosure, the implant provides in vivo culturittg of tissue cells in a diverse tissue or homogeneous lesion, or for non- systemic delivery of one or more therapeutic agents to a patient. The implant provides an electrical component as part of the device and does not include a therapeutic agent component as part of the device, let alone involve delivery of a therapeutic agent to desired tissue.
U.S. Patent Application Publication No 200501 52C>49 discloses a method of intraarticular drug delivery comprising- selecting an attachment zone vάthin the subchondral bone in a synovial joint, affixing a drug release device in the attachment zone, the drug release device comprising a base affixabie in the attachment zone, a sustained release drug carrier and a drug, the device positioned so that the device releases the drug into the synovial fluid of the synovial joint and so thai agitation of the synovial fluid facilitates elution of the drug from the drug release de\ ice One drawback of these implants is that they are fixedly attached to the bone itself in a synovial joint Another drawback of these implants is that many of the intended patients already suffer from pain and inflammation, and will be subjected to more pain upon implantation of the device into the bone and possible formation of osteophytes. Despite the advances recently made in the art, there is an immediate need for improved raedica! devices, methods and systems for targeted delivery of therapeutic agents., such as TNF inhibitors, for the treatment and prevention of inflammation and pain, capable of being delivered for an extended period of time at, or in close proximity to, a 5 targeted site such as the site of trauma or inflammation.
SUMMARY OF THE INVENTION
The present invention fills the foregoing need by providing a drug depot implant comprising a physical structure to facilitate implantation and retention in a synovial joint, a disc space, a spinal canal, or a soft tissue surrounding the spinal canal of a subject; anda I 0 therapeutic agent that creates a concentration gradient for targeted delivers of the agent to the synovial joint, the disc space, the spinal canal, or the soft tissue surrounding the spinal canal, muscle, tendon, ligament, or cartilage of a subject.
One aspect of the present invention, which provides the use of depots to deliver anti-inflammatory or anabolic compounds to intervertebral discs or articulating joints, has i 5 not been previously disclosed. Another aspect of the present invention provides specific designs and methods for insertion of drug depots into discs or joint capsules with minimal tissue disruption and minimal interference with normal joint motion. The methods, systems and reagents of the present invention prevent the depots from migrating away from the inflamed tissue and allow for more uniform distribution of the drug. 0 One aspect of the invention provides a method for reducing pain and/or inflammation, which comprises administering to a target site in a subject in need of treatment an effective amount of a pharmaceutical composition comprising one or more therapeutic agents, wherein the one or more therapeutic agents are administered by a drug depot implant. In one embodiment, the drug depot implant comprises a body that holds 5 the therapeutic agent and an anchoring system that extends from the body to prevent migration of the body from the target site.
One aspect of the present invention provides for a solid depot wherein the therapeutic agent is in lyophilized form within the implant and slowly releases an effective therapeutic amount of agent into the desired location over a prolonged period of time, such 0 as for example, up to and including six months. in the practice of the invention, a drug depot implant is implanted in a subject at or near a target site Non-limiting examples of such sites include an inflamed nerve, a synovial joint, or a spina! site, in particular a spinal disc site, such as the spinal disc space, the spinal canal or the surrounding soil tissue.
In accordance with one aspect of the present invention a drug depot iroplam design provides a physical feature to facilitate implantation and retention of the implant in the desired anatomical location for optimal clinical efficiency. In one embodiment of the invention the drug depot design is a rod shaped implant loaded with a therapeutic agent. One embodiment of the invention provides a rod shaped implant comprising small barbs that minimize migration of the implant in a patient's tissue once implanted
The present invention provides for methods, systems and reagents that permit a surgeon to deliver a drug depot implant with optimal efficiency to a target site in a subject in need of treatment In one embodiment of the invention, the implant is designed to limit '"backoυt" or forward movement into critical tissues In another embodiment of the invention, the implant is positioned in adjacent soft tissue to the spinal foramen space of inflamed nerve roots to alleviate sciatica and/or back pain caused by such inflammation An alternative embodiment of the invention provides for a rod depot implant positioned into a disc space, wherein the implant is positioned in place by the barb. In this embodiment of the invention the rod depot may further comprise a built-in cap or "stop" that positions the rod in place by utilizing an adjacent tissue plane, thereby permitting the active end of the rod to protrude into an aiea of inflamed tissue and elute the therapeutic agent, which may be, for example, an anti-inflammatory agent. In another embodiment of the invention the drug depot implant is positioned in the knee joint, wherein the rod cap is positioned in place by the knee capsule and eiutes the therapeutic agent, such as an antiinflammatory agent, into the knee joint synovial fluid. Additional embodiments of the invention provide for positioning the drug depot implant in the shoulder, hip. other joints or spine of a patient
In one embodiment, a targeted delivery system of one or more therapeutic agents is comenientlv a catheter. In another embodiment, the targeted delivery system is a syringe.
In one method of the invention, the targeted deliver)' system comprises a drag depot implant system administered locally by insertion of a catheter at or near a target site, the catheter having a proximal end and a distal end, the distal end having an opening to deliver a pharmaceutical in situ, the proximal end being fluidly connected to a pharmaceutical delivery pump For example, the proximal end of the catheter may deliver the therapeutic agent to within 10 cm of a target site, or more preferable, to within 5 cm of the target site, or even more preferable, to within 3 cm of the target site In various embodiments of the invention, the therapeutic agent could be delivered to the target site, adjacent to the target site, or from about 0 cm from the target site to about !0 cm from the target site, and may include every distance in-between.
In the employment of an implant of the invention, the therapeutic agent may inhibit inflammation mediated by TNF-α, for example when the therapeutic agent is a TNF-α receptor inhibitor. Suitable therapeutic agents include, but are not limited to, soluble tumor necrosis factor α receptors, pegylated soluble tumor necrosis factor α receptors. monoclonal antibodies, polyclonal antibodies, antibody fragments, COX -2 inhibitors, metatioprotease inhibitors, such as FAPI, gtutamate antagonists, glial cell derived neurotrophic factors (GDNF), B2 receptor antagonists. Substance P receptor (NKl ) antagonists, Downstream regulatory element antagonistic modulator (DREAM), iNOS, inhibitors of tεtrodotoxin (TTX)-resistant Na+ channel receptor subtypes PN 3 and SNS2, inhibitors of interleukiπs, such as IL-1 , 1L-6, 1L-8 and IL-IO, TNF binding protein, dominant-negative TNF variants, Nanobodies®, kinase inhibitors, and combinations thereof. Other suitable therapeutic agents include but are not limited to Adalirouroab, Infliximab, Etanercept, Pegsunercept (I1EG sTNF-RI), Onercept Kineret®, sTNF-Ri, CDP-870, CDP-571. CN1~14<>3, RDP58, ISIS 104838, I -O-β-D-glucans, Lenercept, PEG-sTNFRJl Fc Mutein, D2ΪΪ7, Afelimoraab, AMG 108, 6-methoxy-2-napthylacetic acid) or betamethasone, capsaicin, civamide, TNFRc, ISIS2302 and Gl 129471, integrin antagonists, alpha-4 beta-7 integrin antagonists, cell adhesion inhibitors, interferon gamma antagonists, CTLA4-lg agonists/antagonists (BMS-188667), CD40 ligand antagonists. Humanized anti-IL-o raAb (MIlA, Tocilizumab, Chugai), HMGB- I raAb (Critical Therapeutics Inc.), anti-!L2R antibodies {daclizυmab, basilicimab), ABX (anti IL-8 antibodies), recombinant human IL- IO, l ϊυMax IL- 15 (aiiti~lL 15 antibodies) and combinations thereof. Still other therapeutic agents include, but are not limited to, NF Kappa B inhibitors, such as glucocorticoids including clonidine; nonsteroidal antiinflammatory drugs (NSAIDs), such as salicylates, diflunisai, indomεthacin, ibuprofen. naproxen, tolraetin, ketorolac, diclofenac, ketoprofeπ, fenamates (meienamic acid. medofenamie acid), enoiic acids (piroxicani, nieloxicam), nabumetoπe, celecoxib, etodolac, nimesulide, apazone, gold, sulindac and tepoxalin; antioxidants, such as dithiocarbamate. and other compounds such as sulfasalazine [2-hydroxy-5-[-4-[C2- pyτidinylamiπo)sulfonyl]a2θ]benzoic acid] and steroids, such as ftuocinolone, Cortisol, cortisone, hydrocortisone, fludrocortisone, prednisone, prednisolone, methyl prednisolone, triamcinolone, betamethasone, dexamethasone, beclomethasone and fluticasone In certain embodiments, the therapeutic agent is an osteoinductive factor. Suitable osteoinductive factors include, but are not limited to, a bone morphogenetic protein, a growth differentiation factor or biologically active fragment or variant thereof, a LJM mineralization protein or biologically active fragment or variant thereof, or combinations thereof.
Also disclosed is that the one or more therapeutic agents within the drug depot implant may be incorporated into a sustained release pharmaceutical composition. In one embodiment, two or more therapeutic agents are incorporated into a sustained release pharmaceutical composition For example, in one embodiment two or more therapeutic agents are separately incorporated into separate biocompatible polymers The invention also includes a drug depot implant for treating osteolysis and/or bone resorption comprising administering a drug depot implant to an osteolytic site in a subject in need of treatment, the drug depot implant providing an effective amount of a pharmaceutical composition comprising one or more therapeutic agents, wherein administration of the pharmaceutical composition is localized and sustained. In one embodiment, the one oi more therapeutic agents includes, at least one osteoinductive factor Examples of suitable osteoinductive factors include a bone morphogenetic protein, a growth differentiation factor or a biologically active fragment thereof, a LlM mineralization protein or a biologically active fragment thereof, or combinations thereof.
In yet another embodiment, a method is provided for alleviating pain associated with bone tumors, the method comprising administering to a tumor site in a subject in need of treatment a drug depot implant comprising an effective amount of one or more therapeutic agents, wherein administration of the composition is localized and sustained. In this method the one or more therapeutic agents includes at least one osteoinductive factor Suitable examples include, but are not limited to, a bone morphogenetic protein, a growth differentiation factor or a biologically active fragment or variant thereof, a IJM mineralization protein or a biologically active fragment or variant thereof or combinations thereof δ
Also provided is a system for providing pain relief medication in a mammalian subject, the system comprising a depot for providing controlled and directed delivery of at least one therapeutic agent to a target site in a subject in need thereof comprising an effective amount of a composition comprising at least one therapeutic agent which decreases inflammation at the target site. In another embodiment, the therapeutic agent further comprises a modified release pharmaceutical composition. The system can further comprise two or more therapeutic agents In still another embodiment, a catheter is provided rather than a depot. In this embodiment, a catheter has a proximal end and a distal end, the distal end having an opening to deliver a pharmaceutical in situ, the proximal end being fiddly connected to a pharmaceutical pump In another embodiment, the distal end of the catheter delivers the therapeutic agent within about 10 cm of, or closer to, the target site In another embodiment, the catheter delivers the therapeutic agent within about 5 cm of, or closer to, the target site in this system, the at least one therapeutic agent may inhibit inflammation mediated by TNF-α. Suitable examples of a therapeutic agent is a TNF-α receptor inhibitor, for example, a pegylated soluble TNF-u receptor Other suitable therapeutic agents are listed herein. The system may further comprise a therapeutically effective amount of at least one osteoinductive factor Suitable osteoinductive factors include, but are not limited to. a bone morphogenetic protein, a growth differentiation factor or a biologically active fragment or variant thereof, a LlM mineralization protein or a biologically active fragment or variant thereof, or combinations thereof. In one embodiment the system of the invention employs a depot comprising a modified release pharmaceutical carrier
The invention also includes the use of a composition comprising one or more therapeutic agents that decrease inflammation at a target site for the manufacture of a pharmaceutical for reducing pain, wherein administration of an effective amount of the composition to a target site in a subject in need of treatment is localized and controlled. In one embodiment the invention is a depot for alleviating pain and limiting bone loss associated with osteolysis, wherein the administration of the composition to an osteolytic site in a subject in need of treatment is localized and controlled lii another embodiment the invention includes the use of a composition comprising one or more therapeutic agents that decrease inflammation at a target site for the manufacture of a pharmaceutical for alleviating pain associated with bone tumors, wherein administration of the composition Io a tumor site in a subject in need of treatment is localized and controlled
In any of the above listed uses, the composition may he a sustained release pharmaceutical composition. Also disclosed is a method for retarding tissue necrosis and/or damage, the method comprising administering to a target site in a subject in need of treatment an effective amount of a pharmaceutical composition comprising one or more therapeutic agents, wherein the one or more therapeutic agents are administered by a depot that provides localized and sustained release of the pharmaceutical composition. In one embodiment, the depot is implanted in a subject at or near a target site, such as, but not limited to, an inflamed nene or a spinal site, for example into a spinal disc or spinal disc space.
One aspect of the invention provides a radiographic marker on the drug depot implant to permit a surgeon to accurately position the implant into a tissue of a patient. Examples of such radiographic markers include, but are not limited to, barium, calcium phosphate, and metal beads. Such radiographic markers will also permit the surgeon to track movement and degradation of the implant in the tissue over time In this embodiment of the invention the surgeon may accurately position the implant in the tissue using any of the numerous diagnostic imaging procedures known to one of ordinary skill in the art Such diagnostic imaging procedures include, for example, X-ray imaging or fluoroscopy.
Another aspect of the present invention provides for methods, systems and reagents comprising a drug depot implant configuration for providing a concentration gradient of the therapeutic agent to the tissue of a patient. In this aspect of the invention the preferred drug depot implant is a rod configuration that provides an optimal, therapeutically effecti\ e amount of the therapeutic agent up to about 1 cm to about 5 cm from the rod.
Another aspect of the present invention provides for drug depot implant configurations comprising microspheres loaded with a therapeutic agent, such as a TNF- inhibitor, for targeted delivery' to a desired region of a patient. In this embodiment of the invention, targeted drug depot delivery my be achieved by any means including for example, by injection either into the disc space, the spinal canal, or in the surrounding soft tissues. This embodiment of the present invention delivers the therapeutic agent closer to the inflamed tissue, e g , nerve roots causing sciatic pain, nerve fibers growing into annular tears m discs causing back pain, or knee joints with osteoarthritis It will be appreciated by those with skill in the art that a drug delivery device may he delivered by a wide variety of methods, such as by placement into a drill site, injection by syringe aud/oi catheter or forceful injection by gun These and other objects and advantages of the present invention will be apparent from the descriptions herein. BRIEF DESCRIPTION OF FHE FIGURES
FIG. 1 is a cross-sectional view of one embodiment of a drug depot implant.
FIG. 2 is a cross-sectional view of an alternative embodiment of a drug depot implant
FIG 3 is a side view of another embodiment of a drug depot implant
FIG. 4 shows a targeted delivery device and a drug depot implant.
FIG. 5 is a side view of another drug depot implant.
FIG. 6 shows a drug depot implant with a first embodiment radiographic marker. FIG. 7 shows a drug depot implant with a second embodiment radiographic marker.
FIG. 8 is a side view of an alternative embodiment of a drug depot implant.
Figure 9 illustrates the drug depot implant of FIG 9 deployed in a disk.
Figure 10 illustrates the drug depot implant of FlG. 8 deployed in a joint Figure 1 1 is a side view of another drug depot implant.
Figure 12 is a side view of an alternative ding depot implant
Figure 13 is a side view of yet another alternative of a drug depot implant.
Figure 14 shows the daig depot implant of FIG. 1 1 deployed in a joint.
Figure 15 shows the drug depot implant of FIG 12 deployed in a joint. Figure 16 is a side view of another drug depot implant.
Figure 17 shows the drug depot implant of FIG 16 and an associated targeted delivery system
Figure IS shows the drug depot implant of FlG. 16 deployed in a disc and surrounding soft tissue. Figure ic> shows the drug depot implant of FIG 16 deployed in a joint
Figure 20 illustrates delivery of a therapeutic agent to a spinal canal and surrounding soft tissue utilizing microspheres. Figure 21 illustrates delivery of a therapeutic agent to a synovia! cavity utilizing microspheres.
Figure 22 illustrates delivery of a therapeutic agem to soft tissue surrounding a spinal canal utilizing a gel Figure 23 illustrates delivery of a therapeutic agent to soft tissue surrounding a spinal canal utilizing a gel with dispersed microspheres.
DETA 1 LED DESCRl Pl K)N
For the purposes of promoting an understanding of the principles of the invention. reference will now be made to preferred embodiments and specific language will be used to describe the same it will nevertheless be understood that no limitation of the scope of the invention is thereby intended, such alterations and further modifications of the invention, and such further applications of the principles of the invention as illustrated herein, being contemplated as would normally occur to one skilled in the art to which the in v en ti on relates.
The present invention provides methods, systems and reagents for facilitating implantation of a drug depot implant into a subject comprising implanting an implant depot loaded with a therapeutic agent The drug depot implants of the present invention may be designed for placement and location within oi near the synovial joint, the spinal disc space, the spinal canal or the surrounding soft tissue.
The present invention also provides methods, systems and regents for decreasing, eliminating, or managing pain, especially pain of neuromuscular or skeletal origin, by providing direct and controlled delivery, i.e., targeted delivery of at least one therapeutic, agent to one or more sites of inflammation and sources of pain. A therapeutic agent itself may be on a continuum of rapid acting to long acting Generally, the therapeutic agent is a component of a pharmaceutical composition which can range in a continuum of rapid release to sustained release. Still further, the delivery of that pharmaceutical composition via the targeted delivery system of the invention can include, for example, rapid and repeating deliver}.' at intervals or continuous deliver}-. The delivery can be "local," "direct." and "controlled."
A drug depot implant of the present invention comprises a physical structure to facilitate implantation and retention in a desired location of a subject, such as for example, a synovial joint, a disc space, a spinal canal or a tissue of a subject, and a therapeutic agent that provides a concentralion gradient for targeted delivery of the therapeutic agent to the location In different embodiments, the implant of the present invention provides an optimal drug concentration gradient of the therapeutic agent at a distance from about ! cm to about 5 cm from the implant. The implant of the present invention may further comprise an insertion cannula for delivery of the therapeutic agent to the subject. One aspect of the present invention provides a depot attached to a probe, wherein the probe is released by a pull-back mechanism for delivery of the therapeutic agent to the subject. 'The implant of the present invention may further comprise one or more barbs for minimizing migration of the implant in a tissue of a subject. The implant of the present invention may still further comprise a cap for retaining the depot in a tissue membrane or between tissue planes
An aspect of the present invention provides an injectable drug depot implant comprising microspheres loaded with a therapeutic agent, wherein the microspheres are injected into a synovial joint, a disc space, a spinal canal, or a soft tissue surrounding the spinal canal.
Another aspect of the present invention provides a daig depot implant comprising a gel in viscous form and microspheres loaded with a therapeutic agent, wherein the combination of gel and microspheres are positioned into a synovial joint disc space, a spinal canal, or a soft tissue surrounding the spina! canal of a subject. In one embodiment of the present invention, the gel is a sprayable or injectable adherent gel that solidifies upon contact with tissue
One aspect of the invention provides that the viscous gel loaded with microspheres also delivers the microspheres to the desired inflamed tissue location and prevents the microspheres from being removed from that area by the venous systemic vasculature or otherwise dispersed too widely to get the desired therapeutic effect. In this aspect of the invention, after a few hours or days the gel may be absorbed, thereby allowing the microspheres to begin releasing the therapeutic agent. The microspheres do not begin releasing the agent until they are released from the gel. So, the microspheres must be formed from something that is insoksable or inert in the gel, but soluable or aethe once it comes into contact with the targeted tissue. The gel must be something that dissolves or disperses within the subject tissue As the gel begins to dissolve within hours to days, the microspheres are exposed to body fluids and begin releasing their contents. Examples of gels could be gelatin, PEG, or POE So, the gel could be a different material from the microspheres or the same material, i.e , POE. The gel and microspheres are formulated to optimize exposure time of the tnicospheres and release of the therapeutic agent from the microspheres.
The present invention provides numerous designs for the drug depot One aspect of the invention provides that when depot barbs are employed they can be oriented in one direction to facilitate implantation while also preventing backing out or expulsion of the depot from the desired tissue location. In another aspect of the invention the barbs could also be oriented in opposite directions to prevent movement in either direction once implanted Another aspect of the invention provides that the barbs could be fixed protrusions or flexible protrusions that deflect out once implanted
Another aspect of the invention provides that a joint capsule depot has barbs in combination with a cap such that once the depot is inserted into the wall of the joint capsule the barb deploys and holds the depot in place via the cap and deployed barbs In this aspect of the invention, the barbs keep the depot from backing out and the cap keeps it from completely going into the joint space. In another aspect of the invention the depot can be designed such that the therapeutic agent is embedded only in the portion of the depot protruding into the joint space synovial fluid, hi this aspect of the invention as the joint articulates it facilitates the distribution of the therapeutic agent throughout the synovial fluid In one embodiment, after 3-6 months the depot completely degrades and no longer transverses the joint capsule.
In another aspect of the invention, radiopaque marks are positioned in the depot at opposite ends of the depot to assist in determining the position of the depot relative to the inflamed tissue to be treated. In this aspect of the invention the radiopaque marker could be a spherical shape or a ring around the depot.
The present invention contemplates the use of rod-shaped depots in joint capsules, in which the depots contain one or more sutures for retaining the depot up against the inside of the joint capsule.
The present invention also presides a depot shaped as a tapered rod with a hullet- shaped tip to ease insertion of the depot through the joint capsule tissue and minimize tissue disruption. In this aspect of the invention, the depot may contain a suture that is embedded into a biodegradable rod during manufacture of the depot. In one embodiment of the invention, the suture is strategically positioned within the rod to facilitate positioning the depot adjacent to the inside of the joint capsule
In a further embodiment, a very small hole is made in the John capsule with a blunt probe, then the tapered rod is slowly pushed through this hole, slowly stretching the tissues apart to minimize tissue tearing. Once the rod is fully inserted, the hole in the joint capsule closes upon itself. The suture embedded in the rod is left transversing through the capsule so that it can be pulled taut and knotted up against the outside of the joint capsule, forcing the depot up against the inside of the joint capsule Having the depot up against the inside of the joint capsule will prevent the depot from interfering with normal joint motion. In various embodiments, the suture can exit through the ends of the rod, in the middle, or somewhere in-between. The suture can exit through just one hole through the joint capsule or through two or more holes In a preferred design, the suture exits the rod at two points near the ends of the rod and passes through two points in the joint capsule. This design offers the advantage of holding the depot up against the inside of the joint capsule without rotating and potentially interfering with joint motion
Another aspect of the present invention provides several designs that are contemplated for use in the mtervetebral disc and joint capsules, which includes bead- shaped depots strung together along a suture In this aspect of the invention, the beads may be a drug-loaded biodegradable polymer, and the suture may be either degradable or non-degradable material One embodiment of the invention provides at the leading end of the suture an optional needle or barb to retain the strand within the disc or joint capsule. Another aspect of the invention provides that the strand may be implanted by inserting a cannula, which contains the strand of beads, inside the disc, joint, or soft tissue as far as desired, then deploying the barb into the soil tissue <e.g , the annulus) and slowly retracting the cannula, which will result in the string of beads being pulled from the cannula One embodiment of the invention provides that by fixing the leading edge of the string of beads, the beads are retained at the location where the datg is desired inside a disc, along a nerve root, or transverse across a joint, resulting in a more uniform distribution of the drug. In one embodiment, the string of drug-elutiπg bead depots are disposed along the route of inflamed tissue, thereby resulting in a more effective distribution of the drug and greater clinical effectiveness. For example, a very small hole may be made in an intervertebral disc at the site of a possible disc herniation or in a joint capsule with a blunt probe through which a cannula may he inserted to implant the string of beads. Another aspect of the present invention provides a method for delivering a therapeutic agent to a synovial joint disc space, a spinal canal, or a soft tissue surrounding the spinal canal of a subject, comprising inserting within the synovial joint, the disc space, the spinal canal, or the soft tissue surrounding the spinal canal of a subject, a drug depot implant comprising a hollow depot, the hollow depot comprising a therapeutic agent that provides a concentration gradient for targeted delivery of the agent to the synovia! joint, the disc space, the spinal canal, or the soft tissue surrounding the spinal canal of a subject. One embodiment of the invention provides for an optima! drug concentration gradient extending about 1 cm to about 5 cm from the implant. Another embodiment of the present invention provides for delivering the therapeutic agent to the synovial joint or tissue using an insertion cannula.
Another embodiment of the present invention provides for the drug depot implant further comprising a barb for minimizing migration of the implant in a tissue of a subject, and further comprising a cap for retaining the depot in a tissue membrane or between tissue planes.
Another aspect of the present invention provides a method for delivering a therapeutic agent to a synovial joint, disc space, a spinal canal, or a soft tissue surrounding the spina! canal of a subject, comprising inserting within the synovia! joint the disc space, the spinal canal, or the soil tissue surrounding the spinal canal of a subject a drug depot implant comprising microspheres, the microspheres comprising a therapeutic agent that provides a concentration gradient for targeted delivery of the agent to the subject, wherein the microspheres are injected into the synovia! joint, the disc space, the spina! canal, or the soft tissue surrounding the spinal canal.
Another aspect of the present invention provides a method for delivering a therapeutic agent to a synovial joint, a disc space, a spinal canal, or a soft tissue surrounding the spinal canal of a subject, the method comprising inserting within the synovial joint, the disc space, the spinal canal, or the soft tissue surrounding the spinal canal of a subject a drug depot implant comprising a gel in viscous form and microspheres loaded with a therapeutic agent. The combination of gel and microspheres are positioned into the synovia! joint, the disc space, the spinal canal, or the soft tissue surrounding the spinal canal of a subject In one embodiment of the present invention, the gel is a sprayable or injectable adherent gel that hardens upon contact with tissue.
To aid in the understanding of the invention, the following non-limiting definitions are provided: The terms "comprise," "comprising," "include," "including," "have," and "having" are used in the inclusive, open sense, meaning that additional elements may be included. The terms "such as," "e.g ," and "i.e " as used herein are non-limiting and are for illustrative purposes only "Including" and "including but not limited to" are used interchangeably. As used herein, the term "anabolic compound" is an art-recognized term and referes to any compound that is involved in the synthesis of more complex substances from simpler ones in living tissue.
As used herein, the term "drag delivery device" is an art-recognized term and refers to any medical device suitable for the application of a drug to a targeted organ or anatomic region. The term includes those devices that transport or accomplish the instillation of the compositions towards the targeted organ or anatomic area, even if the device itself is not formulated to include the composition As an example, a needle or a catheter through which the composition is inserted into an anatomic area or into a blood vessel or other structure related to the anatomic area is understood to be a drug delivery device. As a further example, a stent or a shunt or a catheter that has the composition included in its substance or coated on its surface is understood to be a drug deliver)' device A drug delivery device can include a rigid or flexible container. A drug delivers' device may also include a semi-solid composition that releases the daig by dissolution of the device or by leaching of drug from the device. It should also be clear that "implant" covers attaching to the joint in any way, e.g., by implanting into a cavity in bone or cartilage or by suturing or otherwise adhering the device to the surface of bone, tendon, or cartilage.
As used herein, the term "'microspheres'* shall mean generally spherical particles about IO m to about 100 m in size Microspheres comprise a hollow space encapsulated by lipids, polymers, at least one surfactant, or any combination thereof, wherein the hollow space comprises a therapeutic agent. In different embodiments, microspheres may include microbυbbles and liposomes. Aa used herein, the term "osteoinducϋon" refers to the ability Io stimulate the proliferation and differentiation of piuripotent mesenchymal stem cells (MSCs) In endochondral bane formation, stein cells differentiate into cbondrafolasts and chondrocytes, laying down a cartilaginous KCM, which subsequently calcifies and is remodeled into lamellar bone. In intramembraπous bone formation, the stem cells differentiate directly into osteoblasts, which form bone through direct mechanisms. Osteoinduction can be stimulated by osteogenic growth factors, although some ECM proteins can also drive progenitor cells toward the osteogenic phenotype.
As used herein, the term "patient," "SUbJeCt," or "host" refers to a biological system to which a treatment can be administered. A biological system can include, for example, an individual cell, a set of cells (e.g., a cell culture), an organ, or a tissue. Additionally, the term '"patienf can refer to animals, including, without limitation, humans,
As used herein, the term a "targeted delivery' system" is a direct and local administration system to deliver therapeutic agents and includes, but is not limited to. a depot, or a system administered locally by insertion of an implant, catheter or syringe at or near a target site. In some embodiments of the invention, the catheter or syringe is optionally operably connected to a pharmaceutical delivery pump. It is understood that pumps can be internal or external as appropriate A "depot" includes., but is not limited to, capsules, microspheres, particles, gels in viscous forms, coatings, matrices, wafers, pills or other pharmaceutical delivery compositions A depot may comprise a biopolymer that is either biodegradable or nco-degradahie
A "therapeutically effective amount" is such that when administered, the agent results in alteration of the biological activity, such as, for example, inhibition of inflammation The dosage administered to an individual, as single or multiple doses, will vary depending upon a variety of factors, including the agent's pharmacokinetic properties, the route of administration, patient conditions and characteristics (sex, age, body weight, health, size, etc.), extent of symptoms, concurrent treatments, frequency of treatment and the effect desired. Adjustment and manipulation of established dosage ranges are well within the ability of those skilled in the art. as well as in vitro and in vivo methods of determining the alteration of biological activity in an individual, such as the inhibition of TNF or IL-I . According to the invention, the therapeutic agent is used in an amount typically ranging between about 0.1 to 5000 μg/kg of body weight or about 1 to SOOO μg/kg of body weight. Amounts of about SO to 500 μg/kg of body weight are preferred, and amounts of about 50 to 250 μg/kg of body weight are further preferred The term "treating" or '"treatment" of a disease refers to executing a protocol, which may include administering one or more drugs to a patient (human or otherwise), in an effort to alleviate signs or symptoms of the disease. Alleviation can occur prior to signs or symptoms of the disease appearing, as well as after their appearance Thus, "treating" or "treatment" includes "preventing" or "prevention" of disease. In addition, "treating" or "treatment" does not require complete alleviation of signs or symptoms, does not require a cure, and specifically includes protocols that have only a marginal effect on the patient. "Localized" delivery is defined herein as non-systemic delivery wherein one or more therapeutic agents are deposited within a tissue, for example, a nerve root of the nervous system or a region of the brain, or in close proximity (within about 10 cm, or preferably within about 5 an, for example) thereto. "Targeted deliver)' system" pros ides delivery of one or more therapeutic agents in a quantity of pharmaceutical composition that can be deposited at the target site as needed for pain, either continuously or at an intermittent rate.
As used herein, the term "therapeutic agents" refers to pharmacologically active substances, such as those that are direct- and local-acting modulators of pro-inflammatory cytokines such as "TNF-α and IL-I including but not limited to, for example, soluble tumor πeαosis factor α receptors, any pegylated soluble tumor necrosis factor u iccepior, monoclonal or polyclonal antibodies or antibody fragments or combinations thereof.
Examples of suitable therapeutic agents include receptor antagonists, molecules that compete with the receptor for binding to the target molecule, antisense polynucleotides, and inhibitors of transcription of the DNA encoding the target protein. Suitable examples include but are not limited to Ada! imumab. Infliximab, Etanercept, Pegsunercept (PEG sTNF-Ri), sTNF-Ri, CDP-870, CDP-571, CNI-1493, RDP58, ISlS 104838, l -*3-β-D- giucans, Lenercept. S^^G-sI NFRII FC Mutein. D2E7, Afelimomab, and combinations thereof. They can decrease pain through their actions as inhibitors or agonists of the release of pro-inflammatory molecules For example, these substances can act by inhibiting or antagonizing expression or binding of cytokines or other molecules that act in the early inflammatory cascade, often resulting in the downstream release of prostaglandins and leukotrienes. These substances can also act, for example, by blocking or antagonizing the binding of excitatory molecules to nociceptive receptors in the nervous system or neuromuscular system, as these receptors often trigger an inflammatory 10 response to inflammation or injury of the nerve or surrounding tissue through a nitric oxide-mediated mechanism, These therapeutic agents include, for example, inhibitors of the action of tumor necrosis factor alpha (TNF~α). Studies have demonstrated that in chronic arthritic diseases, for example, cartilage degradation continues even when the inflammation has been suppressed. Therapeutic agents such as anti-TNF agents are particularly effective for joint pain, for example, because they not only decrease the inflammation that provides the source of pain but also slow the progression of joint destruction that may accompany the inflammatory response Hence, local targeted delivery of the therapeutic agents in accordance with the invention may reduce tissue necrosis' and damage
Inflammation can be an acute response to trauma or a chronic response to the presence of inflammatory agents. When tissues are damaged, TNF -α attaches to cells to cause them to release other cytokines that cause inflammation. The purpose of the inflammatory cascade is to promote healing of the damaged tissue, but once the tissue is healed the inflammatory process does not necessarily end. Left unchecked, this can lead to degradation of surrounding tissues and associated chronic pain. Thus, pain can become a disease state in itself. That is, when this pathway is activated, inflammation and pain ensue. Often a vicious and seemingly endless cycle of insult, inflammation, and pain sets in. Examples υf conditions in which this cycle is present include, but are not limited to, rheumatoid arthritis, osteoarthritis, carpal tunnel syndrome, lower back pain, lower extremity pain, upper extremity pain, tissue pain and pain associated with injury or repair of cervical, thoracic, and/or lumbar vertebrae or intervertebral discs, rotator cuff, articular joint. TMJ, tendons, ligaments, and muscles.
It is understood that TNF is both affected by upstream events that modulate its production and, in turn, affects downstream events Alternative approaches to treating medical conditions exploit this known fact, and therapeutic agents are designed to specifically target INF as well as molecules upstream, downstream, and/ or a combination thereof. Such approaches include, but are not limited to modulating TNF directly, modulating kinases, inhibiting cell-signaling, manipulating second messenger systems, modulating kinase activation signals, modulating a cluster designator on an inflammatory cell, modulating other receptors on inflammatory cells, blocking transcription or translation of TNF or other targets in pathway, modulating TNF-α post-translational effects, employing gene silencing, and modulating iπtedeukins, for example ΪL- 1. 1L-6 and IL-S As used herein, "modulating" ranges from initiating to shutting down, and within that range is included enhancing significant!} or slightK to inhibiting significant!) OT slightly The term "inhibiting"1 includes a dowiueguiation which ma> i educe or eliminate the targeted function, such as the production of a protein or the translation of an oligonucleotide sequence For example, a given patient's condition may require only inhibition of a single molecule, such as TNF. or modulating rnoie than one molecule in a cascade of upstream and or downstream events in the pathway
In certain embodiments, TNF-α inhibitors reduce chronic discogenic back and !eg pain if delivered fa> perispinal administration In other embodiments, a therapeutic agent is a C 0X2 inhibitor Cyclooxygenase inhibitors are a class of enzymes that are believed to iegulate the synthesis of prostaglandin E2 {PGE2j PGE2 may increase discogenic back pain b> inducing radioculopatln Inhibiting COX enzymes sen es to reduce low back pain While not intending to be bound to a single theory , it is believed that since COX enzymes are iegulators of PGH2s, COX2 inhibitors reduce low back pain by decreasing PGF-2 production One suitable C0X2 inhibitor (6-mcthϋxy-2-naρthylacetic acid) has been shown to suppress PGF.2 production and local inflammation in cell culture as decribcd by M el arange «.'/<?/. ( 1992a), "Λnti-ιnf1amrnator> and gastroinstestinal effects of naburøetone Oi its acti\ c metabolite, 6MNA (&-τnethoxy-2~na|hthylaceiic acid) compaϊison with indomethacin." Agents Actions . Spec No C82-3, and Melarange et a (1992b) "Λnti- irrfl animator) and gastrointestinal effects of nabumetone or its active metabolite, t»~ metho\y-2-naphthylacetic acid (6MNΛ) Comparative studies with mdomethacin," Dig lϊrt. Sc / , 37( 12) 1847- 1 H52 Another PGH2 inhibitor includes betamethasone Another suitable therapeutic agent is a metal loprotease inhibitor For example, TΛPI is a metalloprotease inhibitor \\ hich can block clea\ age of I NF-α which, in turn, will reduce production of TNK-u
Still othei suitable therapeutic agents include glutamate antagonists, glial cell- derived neurotropic factors (GDNF), B2 receptor antagonists, Substance P receptor { NKl } antagonists such as capsaicin and en amide, Dow nstream regulatory element antagonistic modulator (DREAM), ϊNQS, inhibitors of tetrodotoxin (TTX)-resistam Na * -channel receptor subtypes PN3 and SNS2, inhibitors of imerlcukins such as 11. -1. 1L-6 and 1L-8, and anti-inflammatory cy tokines such as IL- IO In one example of an alternative approach, the therapeutic agent is a TNF binding protein One suitable such therapeutic agent is currently referred to as Onercept formulae including Oneicept, Oneicept-like agents, and deiivatn es a*e all considαed acceptable Still other suitable therapeutic agents include dominant-negative TNi: variants A suitable dominant-negative TNF variant includes but is not limited to DK-TNF and including those described by Steed et aL (2003 K 'inactivation of TNF signaling b\ rationally designed dominant-negame FNF v ariants;' Science, 301(5641) 1895-189S Still more embodiments include the use of a recombinant adeno-associated \ iral (rAΛV) \ector technolog\ platform to deliver oligonucleotides encoding inhibitors, enhancers, potentiators, neutralizcrs, or other modifiers For example, in one embodiment an (rA AV) vector techrtologv platfoun is used to deli vet a DNA sequence that is a potent inhibitoi of tumor necrosis factor (TNF-alphaj One suitable inhibitor is TNFR Fc Other therapeutic agents include antibodies, including but not limited to naturalh occurring or synthetic, double-chain, single-chain, or fragments thereof For example, suitable therapeutic agents include molecules that are based on single chain antibodies called Naπobodies© (Abiynx,
Ghent Belgium), which are defined as the smallest functional fragment of a naturally occurring single-domain antibody
Alternatively, therapeutic agents that inhibit kinases and/or inhibit cell signaling aie employed Therapies that fall in this categoϊ} aie capable of manipulating the second messenger s> stems Kinase actuation signals multiple downstream effectors, including those involving phosphatidylinositol 3-kinase and mitogen-actnated protein kinases (MAPK), p38 MAPK. Src and protein tyrosine kinase (PTK) One example includes the signaling of TNF1Gt effects is the downstream activation of MAPK Examples of kinase inhibitors are Glee\ec, liercepiin, ϊressa, imatinib (S 11571 ), herbimycin A, tyrphostin i7. erbstatin, genistem, statsrosporine. PD98O5*3, SB203580,
CM-1493, VX-50/702 (Vertcx/Kissei), SB203580, BlRB 7% (Boehringer Ingelliehn), Glaxo P38 MAP Kinase inhibitor R\VJ(>7t>57 (J&J). UO 126, Gd, SCI0-4W (Scios), RO3201 105 (Roche), Semipimod (Cytokine PharmaSciences) or derivatives of the above mentioned agents Yet another embodiment of the in\ ention pro\ ides for the use of therapeutic agents that block the transcription or translation of TNF -α or other proteins HI the inflammation cascade in acute pain
Therapeutic agents that inhibit TNF-ø post-translational effects are useful in the invention For example, the initiation of TNF-u signaling cascade results in the enhanced production of numerous factors that subsequently act in a paracrine and autocrine fashion to elicit further production of TNF-α as well as other pro-inOamniaiory agents (e.g , IL-I, 1L-6, IL-S, HMG-B I) Extracellular TNF-α modifying therapeutic agents that act on the signals downstream of TNF-α are useful in treating systemic inflammatory diseases Some of these therapeutic agents are designed to block other effector molecules while others block the cellular interaction needed to further induce their production, for example, integrins and eel! -adhesion molecules.
Suitable therapeutic agents include' integrin antagonists, alpha-4 beta-7 integrin antagonists, ceil adhesion inhibitors, interferon gamma antagonists, CTLA4-lg agonists 'antagonists (BM S-! 88667), CD40 ligand antagonists. Humanized anti-IL-6 m Ab
(MRA, Tocilizumab. Chugai ), HMGB-I mAb {Critical Therapeutics Inc.), anti-lL2R antibodies (daclizumab, basiϊicimabj, ABX {anti 1L-8 antibodies), recombinant human IL- SO5 and HuMax I L- 15 (anti-lL 15 antiboies).
Other suitable therapeutic agents include IL-I inhibitors Interleukin-i is a pro- inflammatory cytokine similar in action to TNF-σ. For example, certain inhibitors of this protein are similar to those developed to inhibit TNF-α. One such example is Kineret€* Canalαnra) which ia a recombinant, noπ-giycosylated form of the human inerieukϊn-t receptor antagonist (IL-I Ra). Another suitable therapeutic agent is AMG 108, which is a monoclonal antibody that blocks the action of IL- 1 As mentioned above, pain can become a disease state in itself One particular area in which this is particularly true is in the lower back and legs. For example, disk herniation is a major cause of back pain and sciatica Sciatica, or radiculopathy, is pain that radiates down the back of the iegs and is generally thought to he caused by irritation of the roots of the sciatic nerve. Back pain can also be caused by spinal stenosis, characterized by overgrowth of bony or soft tissue in the spinal canal with associated pressure on the adjacent nerves. Degeneration of the facet joints between the vertebrae, tumors, infections, fractures, and inflammation of surrounding soft tissues can also cause back pain
Forces that damage the vertebrae can injure the spina! cord through stretching, laceration, ischemia, or compression Cancer can metastasize to the spine, resulting in bone destruction and spinal cord compression. Prolonged, continuous pressure on an extremity can result in a crush injury Prior spine surgery, accompanied by the presence of spinal hardware, makes the spine stiff and vulnerable to additional injury. In all these situations, there is an inflammatory response to the injury This response can become the source of significant, and often chronic, pain It is this response that the present invention can address by providing at ieast one inhibitor of an activator of the response The inhibitor or combination of inhibitors is provided at, or in close proximity to. the source of inflammation, and is provided in a sustained dosage that is readily available for delivery at regular intervals, continuously, or as needed to manage the inflammatory response. This dosage can be provided, for example, by means of a controlled administration system. Excitatory amino acids such as giutamate and aspartate have been shown to play a role in the development of pain originating from nerves Mice with blocked giutamate receptors, for example, have been shown to have a reduction in their responses to pain. Giutamate binds to two major classes of receptors, inotropic giutamate receptors (ligand-gated ion channels) and metabotropic receptors { G -protein-coupled receptors). The inotropic receptors in the spinal cord include the N-røethyl-D-aspartie acid (NMDA) receptors, the tt-amino-3-hydroxy-5-methyl-4-isoxazoleρropionate (AMPA) receptors, and the kainite receptors. In the method of the present invention, one or more therapeutic agents can include, for example, antagonists or inhibitors of giutamate binding to NMDA receptors, AMPA receptors, and/or kainate receptors.
Interleukin- 1 receptor antagonists, thalidomide (a TNF-α release inhibitor), thalidomide analogues, (which reduce TNF-α production by macrophages), bone morphogenetic protein (BMP) type 2 and BMP-4 (inhibitors of caspase 8, a TNF-α activator), quinapril (an inhibitor of angiotensin II, which upreguiates TNF-α), interferons such as IL-1 1 (which modulate TNF-α receptor expression), and aurϊn-tricarboxylie acid (which inhibits TNF-α). for example, may also be useful as therapeutic agents for reducing inflammation It is contemplated that where desirable a pegylated form of the above may be used.
Examples of other therapeutic agents include NF kappa B inhibitors such as glucocorticoids, including clonidine, antioxidants, such as dilhiocarbamate, and other compounds, such as sulfasalazine [2-hydroxy-5-[-4-[c2- pyridinylamino]sulfonyi]azo]benzoic acid]. Further examples of suitable therapeutic agents include NSAIDs5 such as tepoxalin, salicylates, difiuiiisaL iπdoroethacin, sulindac, ibuprofen, naproxen, tohnetin, ketorolac, diclofenac, ketoprofen, fenamates (mefenarnic acid, meclofenamic acid), enolic acids (piroxicam, roeloxtcaro), πabumetone. celecoxib, etodolac, nirnesuiide. apazone and gold; other examples include steroids, such as Cortisol, cortisone, hydrocortisone. fludrocortisone, prednisone, prednisolone, meihylprednisolone, triamcinolone, betamethasone, dexamethasone. beclomethasone and fluticasone.
The invention may further provide an implant comprising a pharmaceutical composition comprising one or more biopolymers and at least one therapeutic agent.
Example biopolymers include, but are not limited to, poiy(alpha-hydroxy acids), poly(lactide-co-glycoiide) (PLGA), polyiactide (PLA), polyglycolide (PG), polyethylene glycol (PIΪXT) conjugates of poly(alpha~hydroxy acids), polyorthoesters, polyaspirins, polyphosphagenes, collagen, starch, chitosans, gelatin, alginates, dextrans, vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBT copolymer
(poiyactive), methacrylates, poiy(N-isopropyJacryJamide), PEO-PPO-PEO (plurorøcs), PEO-PPO-PAA copolymers, PLGA-PEO-PLGA, polyphosphoesters, poϊyanhydrides, polyester-anhydrides, poiyamino acids, poiyuretharte-esters. polyphosphates, polycaprolactones, polytrimethylene carbonates, polydioxanones, polyamidc-esters, polyketals, polyacevals, glycosaminoglycans, hyaluronic acid, hyaluronic acid esters, polyethylene- vinyl acetates, silicones, polyurethanes, polypropylene fumarates, polydesamiπotyrosine carbonates, polydesaminotyrosiπe arylates. polydesamiπotyrosine ester carbonates, polydesamnotyrosine ester arylates, polyethylene oxides, polyorthocarboπates, polycarbonates, or copolymers oi physical blends thereof or combinations thereof. The biopoWmer may also provide for non-immediate (i.e., sustained) release. Examples of suitable sustained-release biopolymers include, but are not limited to, poly(alpha-hydroxy acids), ρoly(lactide-co-glycolide) (PiGA), polyiactide (PLA), poiygiycoiide (PG), polyethylene glycol (PEG) conjugates of poly{alpha-hydro.xy acids), polyorthoesters, polyaspirins. polyphosphagenes, collagen, starch, chitosans, gelatin, alginates, dextrans, vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA,
PEGT-PBT copolymer (poiyactive), methacrylates, poly(N-isopropyiacrylamide), PEO- PPO-PEO (piuronics), PEO-PPO-PAA copolymers, PLGA-PEO-PLGA, or combinations thereof.
The present invention also contemplates that a gel may be utilized with the drug depot implant, provided that the gel has a consistency sufficient to hold the therapeutic agent, i.e., be in a viscous form. The therapeutic agent, such as for example BMP, may be provided in freeze-dried form and reconstituted in collagen gel. or any other suitable gel carrier. Any suitable gel carrier capable of delivering the therapeutic agent to the target is contemplated In certain embodiments, the dosage is provided by means of a drug depot implant. implanted to provide the dosage at, or in close proximity to, the target site.
The ability to deliver pharmaceutical compositions comprising therapeutic agents in effective amounts directly to the site of trauma and/or inflammation is problematic in certain respects. As used herein, a pharmaceutical composition comprises at least one therapeutic agent, as part of a drug depot implant and optionally diluents, excipients and other pharmaceutically acceptable agents desirable for improved stability, manufacturing, efficacy and the like
It is desirable that the targeted delivery system be able to accurately, precisely and reliably deliver the intended amount of drug over the intended period of time. Many therapeutic agents are quite expensive, especially those formulated to retain stability and efficacy over extended periods of time. Thus, the ability to efficiently formulate, process, package and deliver the therapeutic agent delivered via the targeted deliver)' system with minima! loss of drug stability and efficacy is desirable, ϊt is desirable that the pharmaceutical compositions suitable for targeted delivery systems of the instant invention be carefully formulated for the desired medical effect in a controlled, local and direct manner Among the features of the invention is the flexibility of the dosing option made possible due to the unique combinations of the controlled administration sγstem(s) and the pharmaceutical compositions. The drug itself may be on a continuum of rapid acting to long acting. Further, the pharmaceutical composition itself can range in a continuum of rapid release or sustained release. Still further, the options for deliver)- of that pharmaceutical composition is on a continuum and includes but is not limited to rapid and repeating deliver)' at intervals ranging to continuous delivery Delivery may occur at a desired site over a desired period of time for adequate distribution and absorption in the patient Advantageously, when the targeted delivery system is implanted, the deliver)' is capable of being directed to sites that are deep, complicated, painful or dangerous to reach by conventional means and /or otherwise inaccessible. As used throughout this specification, the terms "a" and "an" are intended to include the singular as well as plural In one embodiment the invention provides localized deliver)' in a controlled manner, such as that provided by the targeted delivery system of the invention In such an embodiment, the continued up and down cycling of therapeutic agent levels in. the patient can be avoided, allowing the body to adjust more easily to the level of the therapeutic agent. Side effects can therefore be minimized
The targeted delivery system of the invention may additionally include, for example, an infusion pump that administers a pharmaceutical composition through a catheter near the spine or one or more inflamed joints, an implantable mini-pump that can be inserted at an inflammatory site or site of injury or surgery, an implantable control! ed- release device (such as, for example, the device described in United States Patent Number 6,001,386), and a sustained -release delivery system (such as the system described in United States Patent Number 6,007,843 ).
The pharmaceutical composition can also be administered in a controlled and sustained manner by implanting the desired one or more therapeutic agents dispersed within a depot such as polymer matrix that breaks down over time within the tissues, or otherwise incorporated within a protective coating that provides for the delay of the release of the one or more therapeutic agents
One example of a suitable pump is the SynchroMed* (Medtronic, Minneapolis, Minnesota) pump This pump has three sealed chambers One contains an electronic module and battery. The second contains a peristaltic pump and drug reservoir. The third contains an inert gas. which provides the pressure needed to force the pharmaceutical composition into the peristaltic pump. To fill the pump, the pharmaceutical composition is injected through the reservoir fill port to the expandable reservoir The inert gas creates pressure on the reservoir, and the pressure forces the pharmaceutical composition through a filter and into the pump chamber The pharmaceutical composition is then pumped out of the device from the pump chamber and into the catheter, which will direct it for deposit at the target site. The rate of delivery of pharmaceutical composition is controlled by a microprocessor This allows the pump to be used to deliver simi lar or different amounts of pharmaceutical composition continuously, at specific times, or at set intervals between deliveries.
Potential drug delivery devices suitable for adaptation for the method of the invention include but are not limited to those described, for example, in United States
Patent Number 6,551 ,290 ( Elsberry, ci aiX which describes a medical catheter for target specific drug delivery, United States Patent Number 6,571,125 {Thompson}, which describes an implantable medical device for controllably releasing a biologically active agent, United States Patent Number 6,594,880 (Eisberry). which describes an iniraparenchymal infusion catheter system for delivering therapeutic agents to selected sites in an organism; and United States Patent Number 5,752,930 (Rise, et al ), which describes an implantable catheter for infusing equal volumes of agents to spaced sites. Additional designs which may be adapted to be employed in the method of the present invention are provided, for example, in United States Patent Applications such as US 2002/0082583 (a pre-prograrnraable implantable apparatus with a feedback regulated delivery method), US 2004/0106014 (a micro-reservoir osmotic release system for controlled release of chemicals), US 2004/0064088 (a small, light-weight device for delivering liquid medication), US 2004/0082908 (an implantable microminiature infusion device), US 2004/00981 13 (an implantable ceramic valve pump assembly), and US 2004/0065615 (an implantable infusion pump with a collapsible fluid chamber). Alzet* osmotic pumps (Durect Corporation, Cupertino, California) are also av ailable in a variety of sizes, pumping rates and durations suitable for use in the method of the present invention.
The polymers of the present invention may be employed in the preparation of extended-release or sustained release compositions for use in the method of the present invention In one embodiment, further excϊpients are employed The amount of excipient that is useful in the composition of this invention is an amount that serves to uniformly distribute the active agent throughout the composition so that it can be uniformly dispersed when it is to be delivered to a subject in need thereof. It may serve to dilute the therapeutic agent to a concentration at which the therapeutic agent can provide the desired beneficial palliative or curative results while at the same time minimizing any adverse side effects that might occur from too high a concentration It may also have a preservative effect. Thus, for a therapeutic agent that has high physiological activity, more of the excipient will be employed. On the other hand, for a therapeutic agent that exhibits a lower physiological activ ity, a lesser quantity of the excipient will be employed In general, the amount of excipient in the composition will be between about 50% weight (w) and about 99.9% weight of the total composition For therapeutic agents that have a particularly high physiological activity, the amount will be between about 98 0% and about 90.O1J-O weight of the total composition
Delivery of therapeutic agents to decrease or eliminate pain in a human or animal subject by the method and systems of the present invention can be effective for alleviating pain, although amounts of any one or more therapeutic agents administered to a particular subject are at least one order of magnitude iess than those amounts of therapeutic agents, such as TNF-α inhibitors oi antagonists., thai are provided to individuals who undergo systemic infusion or injection By providing one or more therapeutic agents at or in close proximity to the site of inflammation or nerve damage, particularly when those therapeutic agents are provided in a controlled-reiease manner, the amount of therapeutic agents that must be administered in relation to conventional modes of administration, such as oral or by injection, is decreased This increases the pharmaceutical efficiency of the therapeutic agent, because it is being directed to the tissue in which its action will provide the greatest effect, such as a nerve root or region of the brain. While systemic delivery or delivery by intravenous injection may prov ide a sufficient level of therapeutic agent to produce the desired result, it also results in an increased risk of unwanted side-effects, such as risk of infection when anti-TNF-α compositions are repeatedly administered, thus resulting in increases in cost, inconvenience and discomfort to the patient. Effective dosages for use in the method of the present invention can he determined by those of skill in the art, particularly when effective systemic dosages are known for a particular therapeutic agent Dosages may typically be decreased by at least 90% of the usual systemic dose if the therapeutic agent is prov ided as in the method and systems of the present invention. In other embodiments, the dosage is decreased by at least 75%, at least 80%, or at least 85% of the usual systemic dose for a given condition and patient population. Dosage is usually calculated to deliver a minimum amount of one or more therapeutic agents per day. although daily administration is not required. If more than one pharmaceutical composition is administered, the interaction between the same is considered and the dosages calculated Intrathecal dosage, for example, can comprise approximately 10% of the standard oral dosage. Alternatively, an intrathecal dosage is in the range of about 10% to about 25% of the standard oral dosage.
Hie targeted delivery system of the invention can be positioned to deliver at the site of injury which is causing or will cause inflammation, such as a surgical site, or within about 0 5 to about 10 cm, or preferably less than 5 cm, for example, of the injury or inflammatory site. This site can comprise one or multiple sites in the spine, such as between the cervical, thoracic, or lumbar vertebrae, or can comprise one or multiple sites located within the immediate area of inflamed or injured joints, such as the shoulder, hip, or other joints Implantation of the drug depot implant can occur simultaneously with surgery to repair a fracture, remove a tumor, etc- , or can be performed in individuals who experience pain, especially chronic pain, as the result of earlier trauma, injury, surgery, or other initiation of inflammation.
In one embodiment, a targeted delivery system comprises an interbody pump and a catheter, the catheter having a proximal end and a distal end, the distal end having an opening to deliver a pharmaceutical composition in sttu, and a proximal end of the catheter being fluidly connected to the interbody pump.
Tuning of doses can also be determined by a physician or other appropriate health care professional, or the patient, based upon the condition, for example, severity and d urati on of pain Durati on of admi ni strati on of therapeuii c agents, i nterval between d oses, size of dose, continuity or spontaneity of dosage administration, are all appropriately determined by an individual's physician. In deciding the timing of doses the health care professional has options such as administering to a target site in a patient an effective amount of a pharmaceutical composition comprising one or more therapeutic agents, wherein the one or more therapeutic agents are administered by a targeted delivery' system.
The administration can (I j be localized and sustained, (2) occur over a period of at least one day to about 6 months, (3) be continuous or periodic. Further, the health care provider has the choice of selecting a pharmaceutical composition having a targeted release rate. For example, a targeted release rate is from about 24 hours to about 62 days The health care provider may vary the combinations as the patient provides feedback over the treatment course Accordingly, the health care provider lias numerous options not previously available, especially in the treatment of pain, particularly chronic pain
Hie methods, systems and reagents of the present invention may have both human medical and veterinary use, being suitable for use in human children and adults, as well as in other mammals. Implantable controlled-delivery devices or compositions containing therapeutic agents as described herein can be placed during orthopedic surgery to minimize inflammation and associated pain and to decrease the stimulus mat often results in chronic pain, which becomes a disease state in itself
In veterinary use, the targeted delivery system and method of the invention may be useful for decreasing pain associated with orthopedic surgery or injury, or orthopedic or neurological damage associated with infection or inflammation. The method may be especially beneficial for larger animals such as horses, or smaller domestic pets such as cats and dogs For human medical use, the controlled administration system and method of the invention can be used to alleviate pain associated with rotator cuff injury or repair, articular joint pain or repair, temporomandibular joint disorder, tendonitis, rheumatoid and osteoarthritis, carpal tunnel syndrome, ligament pain or repair, or targeted muscular pain relief, for example. Examples of clinical indications for which the invention is appropriate include acute and chronic back and leg pain, whatever the origin. In one embodiment, the therapeutic agent is delivered in the vicinity of an irritated ner\e root at dose lower than current drug dosages The therapeutic agent could be delivered over a period of a few days to several months, depending upon the clinical indication This directed and controlled delivery is beneficial as certain drugs, for example TNF-inhibitors, act to reduce the infection fighting capability of the immune system and therefore can lead to infection and other adverse events. Minimizing the amount of drug (in this case therapeutic agent) and targeting a site of delivery is a significant irøpros ement o\ er what is currently available. Further, the versatility of the treatment options, for example, modifying the dose and deliver)' at will, is unique The health care provider can be more responsive to the patient feedback or changing clinical manifestations. Other inflammatory diseases may also be treated employing the invention. Therapeutic agents can be delivered singly, in combination, in series, or simultaneously. One or multiple disc levels may be Heated at the same lime, with cervical, thoracic, lumbar, or multiple areas being targeted Therapeutic agents may be applied interdiscally, adjacent to the disc, or intramuscularly. Therapeutic agents may be directed to inhibit the effects of TNF-α, cyclooxygenase 2, prostaglandin E2, mediators of inflammation such as glutamate, kinins such as bradykinin, and substance P, for example, as previously described.
The invention is useful in the prevention and treatment of osteoporosis, osteoarthritis and rheumatoid arthritis. For example, rheumatoid arthritis, particularly, is known to have an inflammatory origin, and therapeutic agents, such as inhibitors of the action of TNF -α, can be useful for allev iating pain associated with these conditions, particularly when delivered by the implant and method of the present invention Peri prosthetic osteolysis is a major complication following total joint replacement. Articulating prosthetic joint surfaces and polymethylmethacrylate (PMMA) cement may generate wear particles that cause a chronic inflammatory response and osteoclastic bone resorption (wear debris-induced osteolysis), resulting in mechanical failure of the implant TNF and IL-] have been shown to mediate wear debris-induced, or wear particle-induced. osteolysis Controlled and directed delivery of TNF inhibitors according to the controlled administration system and method of the present invention at an implant site provides a method for preventing implant-associated osteolysis Osteolysis generally, whether wear- induced or caused by other factors, because it often occurs at individual sites such as sites of joint replacement surgery, is an appropriate target for therapy using the controlled administration systems and methods of the invention. Furthermore, because TNF~α has been found to induce osteoclast-Hke ceils and the osteoclast is the cell that resorbs bone, sustained and directed (localized) administration of TNF-α inhibitors, particularly if combined with administration of osteoinductive factors such as BMP, GDF. LMP. or a combination of both, for example, can provide both pain relief and inhibition of bone resorption.
Similarly, malignant or benign tumors of bone are often associated with bone resorption. Where tumors are removed, partially removed, or where a tumor remains, there can be considerable pain. The method and system of the invention provides a means for alleviating such pain and making a cancer patient more comfortable, as well as inhibiting bone resorption or stimulating bone growth at the site.
In one embodiment, the method of the invention can be provided by a targeted delivery system comprising an interbody or similar pharmaceutical pump, an optional catheter fluidϊy connected to the pump to provide a channel for at least one pharmaceutical composition to be transported from the pump to a target site, and a therapeutic quantity of at bast one therapeutic agent such as, for example, a TNF inhibitor. In one embodiment, such a system may also comprise at least one modified release pharmaceutical carrier for the at least one therapeutic agent.
In an alternate embodiment, a depot can comprise at least one modified release pharmaceutical carrier for at least one therapeutic agent, and a therapeutically effective amount of at least one therapeutic agent, such as, for example, a TNF inhibitor Targeted delivery systems can be provided as kits, comprising at least one depot provided in sterile packaging and at least one aliquot of at least one therapeutic agent in a package so that the therapeutic agent is provided in sterile form when introduced into the body. Such kits can also comprise at least one package containing at least one aliquot of at least one therapeutic agent in combination with one or more rπodified-reiease pharmaceutical carriers. Kits can also provide modified-release carriers containing a therapeutic agent within them, the modi fied-iei ease carriers being enclosed or partially enclosed within a matrix or containment device for complete or partial containment of the modified-reiease carriers, the matrix or containment device being provided in sterile packaging and being appropriate for implantation into a target site within the body of a subject in need of therapy utilizing the at least one therapeutic agent. A therapeutically effective amount of an anti-inflammatory agent is administered to a patient in need of said treatment The antiinflammatory agent is selected from the group consisting of TNF, IL-!, IL-6, IL-8, IL- 12, IL-15, IL- 17, IL- 18, GM-CSF, M-CSF, MCP- ! , MIP- 1, RANTES5 ENA-78. OSM5 FGF. PDGF, and VEGF. A variety of antiinflammatory agents contemplated for use in the present invention are described in United States Patent Application Publication 20030176332, which is incorporated herein by reference.
For the purposes herein, "tumor necrosis factor alpha (TNF-α)" refers to a human TNF-α molecule comprising the amino acid sequence as described in Pεnnica et al. Nature, 312.721 (1984) or Aggarwal et al , JBC, 260 2345 (1985). The term "human TNF- α" {abbreviated herein as hTNFα, or simply hTNF), as used herein, also is intended to refer to a human cytokine that exists as a J 7 kD secreted form and a 26 kD membrane associated form, the biologically active form of which is composed of a trimer of noncoΛ aJently bound 17 kD molecules. The structure of hTNFα is described further in. for example, Peunica, D.. et al (1984) Nature 312.724-729, Davis, J M , et al ( ϊ<>87) Biochemistry 26 1322- ! 326, and Jones, E, Y , et al. < 1989) Nature 338:225-228. The term human hTNFα is intended to include recombinant human rhTNFα, which can be prepared by standard recombinant expression methods or purchased commercially (R & D Systems, Catalog No 210-TA. Minneapolis, MN) hTNFα is also referred to as TNF. The term "TNF~α inhibitor" includes agents which interfere with a biological function of TNF-α, generally through binding to TNF-α and neutralizing its activity. Examples of
TNF-α inhibitors include etanercept (Enbrd\ Arngeπ), infliximab (Remicade*, Johnson and Johnson), human anti-TNF monoclonal antibody Adalimumab(D2E7/HUMlRA\ Abbott Laboratories), CDP 571 (Celltech), and CDP 870 (Celltech), as we! J as other compounds which inhibit TNF-α activity, such that when administered to a subject suffering from or at risk of suffering from a disorder in which TNF-α activity is detrimental, the disorder is treated The term also includes each of the aπti-TNF-α human antibodies and antibody portions described in U.S. Pat Nos 6,090,382; 6,258,562, 6,509,015. and in U S patent application Ser. Nos. 00/801. 185 and 10/302,356, each incorporated by reference herein.
In some embodiments., the osteoinductive compositions or factors, used in this. invention as therapeutic agents further comprise a therapeutically effective amount to stimulate or induce bone growth of a substantially pure bone inductive or growth factor or protein in a pharmaceutically acceptable carrier. The preferred osteoinductive factors are the recombinant human bone raorphogenetic proteins (rhBMPs), because they are available in relatively unlimited supply and do not transmit infectious diseases Most preferably, the bone morphogenetic protein is a rhBMP-2, rhBMP-7 or heterodimers thereof. However, any bone morphogeiietic protein is contemplated, including bone morphogenetic proteins designated as BMP-I through BMP-13. BMPs are available from Genetics Institute, Inc., Cambridge, Mass. and may also be prepared by one skilled in the art, as described in U.S. Pat Nos 5. 187.076 to Wozney et al; 5,366,875 to Wozney et al ; 4,877,864 to Wang et al , 5, 108,922 to Wang et al , 5, U 6,738 to Wang et al.; 5,013,649 to Wang et al , 5,106,748 to Wozney et al., and PCT Patent Nos. WO93/0G432 to Wozney et al , WO94-26893 to Celeste et al.; and WO94-26892 to Celeste et al. Osteoinductive factors included within the scope of the present invention are BMP-I . BMP-2, rhBMP~2, BMP-3, BMP-4, rhBMF-4, BMP-5, BMP-6, rhBMP-6. BMP-T[OP-I ], rhBMP-7, BMP-8, BMP-Q. BMP-10, BMP- 1 1 , BM P- 12. BMP-13, BMP- 14, BM P- 15. BMP-16, BMP- 17, BMP-18, Growth and Differentiation Factors. GDF-5, Cartilage Derived Morphogenic
Proteins, LIM mineralization protein, platelet derived growth factor (PDGF), transforming growth factor ' (TCJF- ), insulin-related growth factor-i (IGF-I). insulin-related growth factor-li (IGF-U), fibroblast growth factor (FGF). beta-2-microglobulin (BDGF II), and rhGDF-5, All osteoinductive factors are contemplated whether obtained as above or isolated from bone. Methods for isolating bone morphogenetic protein from bone are described in U S Pat No. 4,294,753 to urist and Urist et a! , Sl PNAS 371 , 1984. Recombinant BMP-2 can be used at a concentration of about 0.4 mg.'ral to about 2.5 mg/ml, preferably near about 1.5 rag/ml However, any bone morphogenetic protein is contemplated, including bone morphogenetic proteins designated as BMP- I through BMP-] 8
The bone growth inductive factor may be supplied as a therapeutic agent for a drug depot implant of the present invention in any suitable manner. The osteogenic factor, preferably BMP, may be provided in freeze-dόed form or in any other suitable liquid or gel carrier. Any suitable medium or carrier capable of delivering the proteins to the implant is contemplated. Preferably, the medium is supplemented with a buffer solution, as is. known in the an.
The term "synovial joint" refers to a moveable articulation of two or more bones The articulation is defined by a synovial cavity, which contains a volume of synovial fluid, is lined with a synovial membrane, and is surrounded by a fibrous capsule. The opposing bone surfaces are each covered with a layer of cartilage The cartilage and synovial fluid reduce friction between the articulating bone surfaces and enable smooth movements. Synovial joints can be further distinguished by their shape, which controls the movements they allow. For example, hinge joints act like the hinge on a door, allowing flexion and extension in just one plane An example is the elbow between the humerus and the ulna. Ball and socket joints, such as the hip, allow movement in several planes simultaneously Condyloid (or ellipsoid) joints, such as the knee, permit motion in more than one plane in some positions but not others. For example, no rotation is possible in the extended knee, but some rotation is possible when the knee is flexed Pivot joints, such as the elbow
{between the radius and the ulna), allow one bone to rotate around another. Saddle joints, such as at the thumb (between the metacarpal and carpal) are so named because of their saddle shape, and allow movement in a variety of directions. Finally, gliding joints, such as in the carpal s of the wrist, allow a wide variety of movement, but not much distance Synovial joints include, but are not limited to, shoulder (glenohumeral and acromioclavicular), elbow (ulno-humerai, radio-capitellar and proximal radioulnar), forearm (radioulnar, radiocarpal, ulnocarpal), wrist (distal radioulnar, radio-carpal, ul no- carpal, mid carpal), hand (carpo-nietacarpal, metacarpophalangeal, interphalangeal), spine (intervertebral), hip. knee, ankle Uibiotaiar, tibiofibular), and foot (talocaicaneai, talonavicular, intertarsal, tarso-meratarsal, metatarsal-phalangeal, interphalangeai).
In some embodiments, for example, implants may be formed from hydrophilic materials, such as hydrogels. or may be formed from biocompatible etastomeric materials known in the art, including silicone, polyurethane, polyolefins such as polyisobutylene and polyisoprene. copolymers of silicone and polyurethane, neoprene, nitrile. vulcanized rubber and combinations thereof. In a preferred embodiment the vulcanized rubber is produced by a vulcanization process utilizing a copolymer produced, for example, as in U.S. Pat. No. 5,245,098 to Summers et a!., from 1-hexene and 5-methyl-1.4-hexadiene. Preferred hydrophilic materials are hydrogels. Suitable hydrogels include natural hydrogels, and those formed from poi) vinyl alcohoi, aciylamides such as polyacrylic acid and poly (acrylomiriie-acrylic acid).
Figure imgf000036_0001
pyπolidone), aαylates such as
Figure imgf000036_0002
ethyl methaciyiate) and copohmeis of acrj lates with N-vim ! pj roϋdone.
Figure imgf000036_0003
lactams. acry!amide, polyurethanes and polyacrylonitrile or may be foimed from other similar materials that foim a hydrogel The
In drogel materials may further be cross-linked to provide further strength Io the implant Examples of different types of poiyurethan.es include thermoplastic or thermoset pohurethanes, aliphatic or aromatic poWurethanes. poi\ etherurethane, poKcarhonate- urethane and silicone pol\ ether-urethane Other suitable hvdrophilic polymers include naturally-occurring materials such as glucomannan gel hyaluronic acid, polysaccharides, such as cross-linked
Figure imgf000036_0004
l-containing pol> saccharides, and combinations theieof
The implants of the invention ma> be made of at least in part of a biocompatible material Furthermore, in some embodiments, the implants rπa> be made of an implantable material, such as a material suitable for implantation in bone, implantation in cartilage, and/or implantation in other hiornaterials in a joint In particular, the implant may be formed at least in part of a material that can maintain its integrity during implantation This may help prevent leakage of a drug in the carriei through a crack or fissure in the implant In some embodiments, the implant reservoir may be constructed Horn a metal, such as titanium, nickel titanium, stainless steel, anodi/ed aluminum, oi tantalum, or a plastic, such as
Figure imgf000036_0005
lene, nylon, or poWurethane The implant may also include a material oi modified material to allow for osseous mtcgiation of the implant, i e , bone ingrowth Other suitable materials will be apparent to one of ordinary skill in the art Moreover, combinations of materials may be used
T he implants of the imention may be provided with surface features defined in their outer surfaces For example, a projection may be formed on the end w alls instead of a slot Such a projection may form a straight, flat-sided shape, an elliptical eminence, a biconcave eminence, a square eminence, ot am othei piotiuding shape which provides sufficient end-cap or tool-engaging end strength and drive purchase to allow transmission of insertionai torque without breaking or otherwise damaging the eminence Yet other surface features can be defined on the implant As mentioned above, the outer surface of the implant may define barbs or other surface features that may stabilize the diug depot implant interface with tissue and reduce micromotion The drug depot implants of the present invention may be designed for placement and location within or near the synovial joint, spina! disc space, spinal canal or the surrounding soft tissue. In some embodiments, the contemplated placement and location areas of the drug depot implants within the desired location of the subject will not cause damage to the bone, cartilage surface or tissue, as it may be placed and secured using an anchoring device,
In some embodiments, placement of the device in a patient may be an intraarticular region of a synovial joint where there is no interfacing articular cartilage. It may be located, for example, within the inside of the knee capsule that is non-load-bearing and removed from the articulation surface of the synovial joint The device may be attached within the synovial joint, allowing for continuous exposure to syno\ iai fluid flow and resulting release of anti-inflammatory or osteogenic therapeutic agents, without damaging the articular surface that is in apposition during range of motion of the given joint According to another embodiment of the present invention, the therapeutic agent, e.g., an ti -inflammatory agent or osteoinductive factor, can be packaged into gas-filled lipid- containing microspheres. The gas-filled lipid-containing microspheres may further comprise biocompatible polymers on their outer surfaces The present invention provides that the therapeutic agent may also be contained in a freeze dried state within the microsphere to preserve its stability and activity over an extended period of time. Si mil ar!y. the present invention also provides that the therapeutic agent may be contained in a freeze dried state within the depots to preserve it's stability and activity over an extended period of time.
Non-limiting examples of suitable gases are air, nitrogen, carbon dioxide, oxygen, argon, fluorine, xenon, neon, helium, or any and all combinations thereof Furthermore, various flυorinated gaseous compounds, such as various perfluorocarbon, hydrofiuorocarboπ, and sulfur hexafiuoride gases may be utilized in the preparation of the gas filled microspheres.
For the biocompatible lipid materials, it is preferred that such lipid materials be what is often referred to as "amphophilic" in nature (i.e . polar lipid), by which is meant any composition of matter which has, on the one hand, lipophilic, i.e , hydrophobic properties, while on the other hand, and at the same time, having hydrophilic properties The lipid may alternatively be in the form of a monolayer, and the monolayer lipids may be used to form a single monolayer (unilamellar) arrangement. Alternatively, the monolayer lipid may be used Io form a series of concentric monolayers, i e , oligoiamellar or multilamellar, and such arrangements are also considered to be within the scope of the i nvention
Non-limiting examples of suitable lipids are fatty acids, iysolipids, phosphatidylcholine with both saturated and unsaturated lipids, dimyristoylphosphatidylchoUne, dipentadecanoyiphosphatidyϊchoiine. dϋ auroy 1 phosphatidy lchol ine, di patmitoy 1 phosphat i dy 1 chol i ne (DPPC ), distearoySphosphatidyleholine (DSPC). phosphatidylethanolamines, phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, sphingolipidsglycolipids, glυcolipids. sulfatides, glycosphingolipids, phosphatidic acids, palmitic acid, stearic acid, arachidonic acid, oleic acid, lipids bearing polymers, lipids bearing sulfonated mono-, di-, oligo- or polysaccharides, cholesterol, cholesterol sulfate and cholesterol hemi succinate, tocopherol hemisuccinatε. lipids with ether and ester-linked fatty acids, polymerized lipids, diacetyl phosphate, dicetyl phosphate, stearylamine, cardioiipin, phospholipids with short chain fatty acids of 6-8 carbons in length, synthetic phospholipids with asymmetric acyl chains
(e.g , with one acyl chairs of 6 carbons and another acyl chain of 12 carbons), ceramides, non-ionic liposomes, polyoxyethyleπe fatty alcohols, polyoxyethylene fatty alcohol ethers, polyoxyethylated sorbitan fatty acid esters, glycerol polyethylene glycol oxystearate. glycerol polyethylene glycol ricinoleate, ethυxylaied soybean sterols, ethoxylated castor oil, polyoxyethylene-polyoxypropyiene polymers, and polyoxyethylene fatty acid stearates; sterol aliphatic acid esters including cholesterol sulfate, cholesterol bυtyrate, cholesterol iso-butyrate, cholesterol paimitate, cholesterol stearate. lanosterol acetate, ergosterol paimitate, and phytosteroi n-butyrate, sterol esters of sugar acids, esters of sugar acids and alcohols, esters of sugars and aliphatic acids, saponins, glycerol dilaurate, glycerol trilaurate, glycerol dipalmitate, glycerol and glycerol esters, longchain alcohols, djgalactosyldiglyceride, 6~{5-cholesten~3 beta -ylo\y)hexyS-o-anuno~6-deoxy-1 -thio- .beta.-D-gaiacto pyranosϊde, 6-(5-choiesten-3 beta -yJoxv)hexyl-6-amino-c>-deoxyl-l-thio- alpha -D-manno pyranoside, 12-(((7'-diethy]aminocoumarin-3-yl)carbonyl)methylamino)- octadεcanoic acid, N->12-(((71-diethylarainocouniarin-3-yl)carbonyl)metliyl-aniuio) octadecanoyl !-2-aniinopaln«tic acid, cholester)'3)4'-trimethylaramoπio)bυtanoate, N- succi ny I di ol eoylphosphati dy 1 ethanol am in e, 1 , 3 -di pa! m i toy I -2-succinylgly cerol . and/or combinations thereof Polymers suitable for this embodiment of the present invention can be natural, semi- synthetic or synthetic. Exemplary natural polymers suitable for use in the present invention include naturally occurring polysaccharides, such as for example, ambinans, fructans, fucans, galactans, galacturonans. glueans, mannans, xylans (such as, for example. inulin), levaπ, fueoidars, carrageenan, gaiatocarolose, pectic acid, pectin, amylose, pullυlan, glycogen, ainylopecύn, cellulose, dextran, pustulan, chiύn, agarose, keratao, chondroitan, dermatan, hyaluronic acid, alginic acid, xaπthan gum, starch and various other natural homopolymer or heteropolyrnerx such as those containing one or more of the following aldoses, ketoses, acids or amines: erythrose, threose, ribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose, gυlose, idose, galactose, talose, erythmlose, rϊbulose, xylulose, psϊcose, fructose, sorbose, tagatose, rnannitoL sorbitol, lactose, sucrose, trehalose, maltose, cell obi ose, glycine, serine, threonine, cysteine, tyrosine, asparagine, gSutainine, aspartic acid, glutamic acid, lysine, arginine, histidinε. glucuronic acid, gluconic acid, glucaric acid, galacturonic acid, mannuronic acid, glucosamine, galactosamiiie, and neuraminic acid, and naturally occurring derivatives thereof.
Exemplary semi-synthetic polymers include carboxymethylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, methylcelluloae, and raetlioxycellulose. Exemplary synthetic polymers suitable for use in the present invention include polyethyien.es (such as, for example, polyethylene glycol, polyoxyetliylene, and polyethylene ierephthiaie), poly propylenes (such as, for example, polypropylene glycol), polyurethanes (such as, for example, polyvinyl alcohol (PVA), polyvinylchloride and polyvinylpyrrolidone), polyamides including nylon, polystyrene, poiylactic acids, fluorinated hydrocarbons, fluorinated carbons (such as, for example, polytetrafiuoroethyleneX and polymethylmethacrylate, and derivatives thereof. The gas-filled lipid-containing microspheres of the present embodiment can be prepared, for example, by shaking an aqueous solution comprising a lipid in the presence of a gas at a temperature below the gel state to liquid crystalline state phase transition temperature of the lipid. The shaking must be of sufficient force to result in the formation of microspheres, particularity stabilized microspheres. The shaking may be by swirling. such as by vortexing, side-to-side, or up-and-down motion. Different types of motion may be combined. Also, the shaking may occur by shaking the container holding the aqueous lipid solution, or by shaking the aqueous solution within the container without shaking the container itself. It is preferred that the motion be reciprocating in the form of an arc between about 2 degrees and about 20 degrees, more preferably, about 6 5 degrees. It is contemplated that both the arc and the rate of reciprocation are critical to determining the amount and size of the gas and gaseous precursor filled microspheres formed. It is a preferred embodiment of the present invention that the number of reciprocations, i.e . fuM cycle oscillations, be within the range of about 1000 to about 20,000 per minute.
It would be apparent to a person skilled in the art that other techniques of making the gas-filled lipid-containing microspheres of the present embodiment are available One can create such microspheres by using freeze-thaw, as well as techniques such as sonication, chelate dialysis, homogenization, solvent infusion, microemulsification, spontaneous formation, solvent vaporization, French pressure cell technique, controlled detergent dialysis, and other known techniques.
The gas and gaseous precursor filled microspheres made by the method described above can then be sized by optical microscopy. It should be determined that the largest size of the microspheres ranges from about 50 to about 60 m and the smallest size detected should be about S . m The average size should range from about 15 to about 20 m The gas and gaseous precursor tilled microspheres may then be filtered through an 8, 10 or 12 ni "NUCLEPORE" membrane using a Swin-Lok Filter Holder, ("Nuclepore Filtration Products, Oostar Corp., Cambridge, Mass.) and a 20 cc syringe (Becton Dickinson &. Co , Rutherford, NJ.). The membrane may be a 10 or 12 . "m "NUCLEPORE" membrane (Nuclepore Filtration Products, Costar Corp., Cambridge,
Mass.). The 10.0 m filter is> placed in the Swin-Lok Filter Holder and the cap tightened down securely. The lipid-hased microsphere solution is shaken up and it is transferred to the 20 cc syringe via an IS gauge needle Approximately 12 ml of gas-filled foam solution may be placed in the syringe, and the syringe screwed onto the Swin-Lok Filter Holder. The syringe and the filter holder assembly are inverted so that the larger of the gas and gaseous precursor filled microspheres can rise to the top. Then, the syringe is gently pushed up and the gas and gaseous precursor filled microspheres are filtered in this manner.
The survival rate (the amount of the gas and gaseous precursor filled microspheres that are retained after the extrusion process) of the gas and gaseous precursor filled microspheres after the extrusion through the 10.0 . m filter is about 83-92% Before hand extaision, the volume of foam is about 12 ml and the volume of aqueous solution is about 4 ml. After hand extrusion, the volume of foam ia about 10-S l mi and the volume of aqueous solution is about 4 mi
The optica! microscope may be used again to determine the si/.e distribution of the extruded gas and gaseous precursor filled microspheres, ϊt is determined that the largest size of the microspheres ranges from about 25 to about 30 m and the smallest size detected is about 5 m. The average size ranges from about 8 to about 15 m. Specific embodiments according to the methods of the present invention will now be described in the following non-limiting examples, ϊt is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as defined by the claims. In one specific application, the present invention contemplates drag depot implants as depicted in FlG. 1. FlG. 1 is a cross-sectional view of a rod-shaped drug depot implant 10 comprising one or more small barbs 12 that serve as anchoring devices to minimize migration of the implant in a patient's tissue once implanted In the following, the term "rod-shaped" is intended Io indicate any shape with a longitudinal axis, i e.. is longer along one direction than in other directions, the cross- sectional shape across the longitudinal axis may be any shape, but is preferably elliptical or circular The rod-shaped implant's length can range from about 1 mm to about 10 cm; its diameter can range from about 0 5 mm to about 5 cm. A preferable length may be from about 2 cm to about 10 cm with a preferable diameter ranging from about 1 mm to about 2 mm Alternative preferable length can range from about 2 cm to about 10 cm; with an alternative preferable diameter ranging from about 2 mm to about 1 cm. 'The implant 10 comprises a rod-shaped {or bullet-shaped) body 14 that is made from a biodegradable material. In alternative embodiments, the body may be made from a non-biodegradable material. A nonbiodegradable body could be a porous hollow chamber filled with the therapeutic agent alone or incorporated into a degradable polymer. It may be desirable to make the body non-degradable to be able to retrieve it after it has released its contents Or the non- biodegradable body could be a small pump that pushes the contents out pores, port(s), or a cannula Non-limiting examples of suitable biodegradable materials for the body 14 include polyorthoesters (POE), polylactkglycolic acid (PLGA) polysaccharides (Saber technology), polycapralactone, polyfemarate, tyrosine polycarbonate, etc The body 14 is solid, and a therapeutic agent 16 ia dispersed throughout the material that forms the body 14. The dispersal of the therapeutic agent 16 may be even throughout the body i4 Alternatively, the concentration υf die therapeutic agent 16 may vary as a function of the distance from the longitudinal centerline 18 of the body 14, or as a function of a distance along the longitudinal centerline IS. As the biodegradable material of the body 14 degrades within the tissue, the therapeutic agent 16 is released. Suitable sustained release materials may be used for the body 14 to carry the one or more therapeutic agents 16 and control the release of the therapeutic agent(s) 16 For example, microspheres may be used to encapsulate the therapeutic agent; the therapeutic agent-containing microspheres are then dispersed through the body 14 The one or more barbs 12 serve as an anchoring system and are designed to permit forward translati ona! movement of the body 14 along the longitudinal axis 18, while retarding backward traiislational movement. Specifically, the barbs 12 extend from the body 14 and point backwards along the longitudinal axis 18. The barbs 12 may be made from the same material from which the body 14 is made, or from a different material. For example, the barbs 12 may be made from a secondary material that degrades more slowly than the primary material of the body 14, and attach to a core of such secondary materia! that runs through the longitudinal centerline 18 of the body 14 The present invention provides other designs for gradient variations in biodegiadafoilUiy to hold the depot in place while the secondary material releases it's contents. The baits could be a "snap-on" component that tits over the depot containing the therapeutic agent In this, embodiment the manufacturing of the drug loaded depot is made easier instead of having to injection mold the barbs into the depot. The barbs 12 may be axially aligned or circumferential]}' spaced in relation to each other about the daig depot implant 10. in certain embodiments, the implant 10 may be designed to be affixable within a joint. The implant 10 may have a width from about 1 mm to about 6 mm and a length from about 5 mm to about 20 mm Selection of suitable lengths and widths for the device 10 will depend upon the targeted implant site, and is well within the abilities of those having ordinary skill in the art.
FiG, l is a cross- sectional view of another implant 20 As with the previous example, the implant 20 comprises one or more barbs 22 that permit forward motion of the implant 20 while retarding backward motion, thus serving as an anchoring system to anchor the implant 20 within the targeted deliver)' site. The implant 20 comprises a rod- shaped shell 24 that is made from a non-biodegradable material, such as polyethylene. delrin, polyurethane. Alternatively, the shell 24 may be made from a biodegradable material that degrades relatively slowly within the implant site. Suitable biodegradable materials, include POE5 PLGA, PLA, PGA5 and all the oilier standard degiadable polymers The shell 24 forms a cavity 25, and one or more therapeutic agents 26 are disposed within the cavity 25, The therapeutic agents 26 may be, for example, in freeze- dried form, dispersed in a carrier, contained within microspheres, or packed in any other suitable manner within the cavity 25 The shell 24 is permeable to the therapeutic agent 265 however packed, so that the therapeutic agent 26 can diffuse through the shell 24 and into the surrounding tissue. For example, in the case where the shell 24 holds therapeutic agent-containing microspheres, the shell 24 may comprise a plurality of pores through which the microspheres may pass to subsequently release the therapeutic agent in or near the targeted tissue. Alternatively, the microspheres may release the therapeutic agent within the shell 24, and then the therapeutic agent may diffuse through the shell 24 to the targeted tissue through pores or be hydrolocally pumped out of the device. The diffusion rate of the therapeutic agent 26 may be controlled by the thickness of the shell 24. by the number and diameter of the pores within the shell 24, or by the concentration of the therapeutic agent or the medium (gelatin. POE, PLGA. etc ) in which the therapeutic agent is embedded The barbs 22 may be made from the same material as the shell 24 and may be disposed in any suitable maunei about the ouiei surface of the shell 24. If the shell 24 is made from a biodegradable material, the type and thickness of the material used should be sufficient to ensure that all, or nearly all, of the therapeutic agent 26 has dispersed into the surrounding tissue before the integrity of shell 24 is substantially compromised.
FIG. 3 is a side view of another implant 30. The implant 30 may be solid, as in the implant 10, or shell-like, as in the implant 20. The implant 30 has a rod-shaped outer surface 34 from which a therapeutic agent, contained internally of the outer surface 34, diffuses, as discussed above. Extending from the outer surface 34 are one or more first barbs 32 and one or more second barbs 36. The first barbs 32 point backwards along the longitudinal axis 38 to prevent backward movement of the implant 30 (i e., movement opposite to the direction indicated by longitudinal centerline arrow 38); the second barbs 36 point forwards along the longitudinal axis 38 to prevent forward movement of the implant 30 (i.e , movement along the longitudinal centerline arrow 3S). The baits 32, 36 thus serve as an anchoring system to keep the implant 30 at the targeted delivery site, that is, the anchoring systems prevent both forward and backward lranslational movement of the implant 30
The barbs 12, 22. 32, 36 in the above examples may be flexible, that is, they may be compressible towards the centerline of the longitudinal axis 18, 28. 38 This may assist in the targeted delivery of the implant 10, 20, 30. For example, as shewn in FIG. 4, an implant 40 may be released at a target site by a targeted delivery system 41 , which may be a catheter, a syringe, or any other suitable de\ ice As shown, the targeted delivery system 41 may include a cannula 43 in which, the implant 40 is disposed. The implant 40 has flexible barbs 42 that extent as they exit from the cannula Ai. FIG. 5 is a side view of another embodiment implant 50. The implant 50 has a rod-shaped outer surface 54 from which elutes a therapeutic, agent contained therein. Extending from the outer surface 54 is one or more extensions 52 adapted to prevent both forward and backward transSational movement of the implant 50, and which thus serve as an anchoring system to keep the implant 50 at the targeted delivery site The extensions 52 may be flexible, and hence may extend once released from a targeted delivery device.
The extensions 52 point substantially 90 degrees away from the longitudinal axis 58. The anchoring system provided by the extensions 52 may also prevent rotational movement of the implant 50
Implants of the present invention may contain radiographic markers, that assist in the imaging of the implants, and hence in the targeted delivery of the implants. The radiographic markers may be made from any suitable material, as previously discussed, and may be, for example, ring-shaped or dispersed as small peilets throughout the implant An implant 60 utilizing ring-shaped radiographic markers is depicted in FIG. 6 As shown, one or more radiographicalSy active rings 62 are positioned in or on the body 64 of the implant 60. Each ring 62 is placed at a predetermined position within the body 64, and thus when imaged enables a physician to determine the position and orientation of the implant 60. FlG 7 presents another possible embodiment for radiographic markers as applied to an implant of the present invention. An implant 70 comprises a body portion 74 that holds and elutes the therapeutic agent. Regularly dispersed throughout, or on, the body portion 74 are small beads 72 of a radiographically active substance. Imaging of the beads 72 provides a clear indication of the position and orientation of the body portion 74 within the target tissue. Alternatively, the beads 72 may be disposed in or on the body portion 74 according to a predetermined pattern; imaging of this pattern presented by the beads 72 will similarly provide solid reference for the position and orientation of the body portion 74,
FlG. 8 is a side view of another implant 80. The implant 80 has a rod-shaped body portion 84, which may be tapered, from which extends a first anchoring system 82 and a second anchoring system 86 that secure the implant 80 within the targeted tissue location.
The first anchoring system 82 is configured as one or more barbs 82, which point backwards with respect to the forward (or insertion) direction indicated by longitudinal centerline arrow 88 The barbs 82 thus prevent the implant 80 from backing out of the implant site. The barbs 82 may be flexible The second anchoring system 86 is an end cap 86 that is adapted to abut against a tissue plane. A forward surface 89 of the enά cap
86 contacts the tissue plane, and thus prevents forward translations! movement as indicated by centerline arrow 88, of the implant 80. Both the barbs 82 and the end cap 86 may be made from the same material as the body potion 84 The body portion 84 may be hollow or solid and may or may not be biodegradable, as described previously. The body portion S4 contains and elutes the desired therapeutic agent Although the therapeutic agent may be dispersed throughout the body portion 84 as well as throughout the barbs 82 and end cap 86, it may be desirable to dispose the therapeutic agent only within a forward region of the body portion 84. For example, it may be desirable to dispose the therapeutic agent only within the forward two-thirds of the body portion 84, as indicated by arrow 8 ! . Alternatively, it may be desirable to have the therapeutic agent in only the forward half of the body portion, as indicated by arrow 83, or only the forward third, as indicated by arrow 85. Indeed, it may be desirable to have the therapeutic agent disposed only within a tip region 87 of the body portion 84. Hence, depending upon the region 81, 83, 85, 87 selected, the therapeutic agent will only eiute from that specific region 81. 83, 85, 87 of the implant 80. The forward end 81, 83, 85. 87 of the body portion 84 that contains the therapeutic agent may be termed the active end of the implant 80. The end cap 86 may be formed with the body portion 84, Le , be monolithic with the body portion 84, or may be provided as a separate element. If provided as a separate element, the end cap 86 and body portion 84 should have corresponding mating elements that enable a physician to attach the end cap 86 to the body portion 84 after the body portion 84 has been deployed at a targeted tissue site Any suitable mating system may be used such as for example, mechanical snap-on or threaded fixation. As shown in FfG 9, an implant 90 of the instant invention may be disposed in a disc 91 to alleviate diskogenic pain A disc 91 to be treated is sandwiched between two vertebrae 93 The implant 90 is. inserted into the interior region υf the disc 91, such as the annular fibrosius or nucleus* pulposus of the disc 01. This* embodiment is achieved for example as shewn in FIG. 4, through a hollow cannula. The cannula is withdraw, deploying the barbs. The implant 90 has an anchoring system 02 that extends from the impiant QG to keep the implant 90 firmly constrained to the targeted tissue site, preventing forward and backwards movement of the implant 90 within the disc 9 ! , The implant 90 also has an active region 94 that elutes a therapeutic agent 96 into the disc 91. The concentration gradient of the eluted therapeutic agent 96 may extend from 1 cm to as far as S cm from the active region 94 of the implant 90.
The implant 80 of FIG. 8 is shown deployed in the synovial cavity 102 of a synovial joint 100 in FlG 10 The joint 100 depicted is an idealized synovial joint but roughly approximates the femur-tibia articulation at the knee. Exemplar}' placement of the impiant SO is indicated In this example, the placement of the implant 80 is in the joint and is remote from the bone. As shown, the forward surface 89 of the end cap 86 abuts against the synovial membrane 104, thus preventing forward movement of the implant 80 into the joint 100. Similarly, the barbs 82 prevent the implant 80 from backing out of the joint 100. An active end 106 of the implant 80 elutes a therapeutic agent 108 into the synovial fluid of the cavity 102.
FIG. 1 1 is a side view of another implant 110. The implant 110 comprises a tapered, rod-shaped body portion 1 14 and a suture 1 12 that extends from the body 1 14 The body 1 14 may be hollow or solid, as previously described, and may be made from a biodegradable or non -biodegradable material The body 1 14 contains, and elutes, a therapeutic agent. The entire body 1 14 may be active (i.e., elute the therapeutic agent), or instead may have an active region in a predetermined position, as indicated earlier for other embodiments. The suture 1 12 may be made from a biodegradable or nonbiodegradable material. If made from a biodegradable material, it may be desirable to select a material for the suture 112 that degrades significantly slower than the body 1 14 As shown, the suture \ 12 enters from a central region 116 of the body 114, substantially circumnavigates the body 1 14, and then exits from the central region 1 16. The suture 1 12, extending from the body portion 1 14, serves as an anchoring system for the implant 1 10. By tying the suture 1 12 onto adjacent tissue, it is possible to securely retain the implant 1 10 at a targeted tissue site, and hence prevent traπslational movement of the implant 1 1 O within or from the targeted tissue site
FlG 12 shows another implant 120 that similar!) utilizes a suture 122 As in the implant 110, the suture 122 may traverse just under the body portion 124 In the implant 120. however, the suture 122 enters the body portion 124 from a first end region 126 of the bod\ 124 and exits. Horn a second end region 128 of the bod) 124 The end legions 126, 128 ma> include, for example, the outer third of the body portion 124. with respect to the longitudinal axis 129
Another embodiment implant 130 is shown in FIG 13 For the implant 130, the suture 132 enters at or near a first cndpoint 136 of the body 134, traverses within the body
134 substantially along the longitudinal centeiline IW, and exits flora, or near, a second cndpoint 138 of the body 124 The cndpoints 136, 138 are defined by the longitudinal centerline 139 of the body 134
It is contemplated that the several drug depot designs 1 10, 120, 130 may be used i n joint capsules, with the sutures 1 12, 122, 132 being used to reiain the depot 1 10, 120, 130 up against the inside of the joint capsule FIG 14 shows, for example, deployment of the implant 1 10 of FIG 1 1 in a synovial joint 140 The bullet-shaped tip of the body 1 14 eases insertion of the implant 1 10 through the joint capsule tissue 142 and minimizes tissue disHψtion A very small hole is made in the joint capsule 142 with a blunt piobe, and then the tapered rod i 14 is slo\\i\ pushed through this hole, slow l\ stretching the tissues apart to minimize tissue tearing Once the rod 1 14 is full) inserted, the hole in the joint capsule 142 closes upon itself The suture 1 12 embedded in the rod 1 14 is left passing through the capsule 142 so that it can be pulled taut and knotted up against the outside of the joint capsule 142, forcing the depot 1 K* up against the inside of the joint capsule 142 Having the depot 110 up against the inside of the joint capsule 142 will prevent the depot 1 10 from interfering with noimal joint 140 motion
HG 15 shows the implant 120 of FlG 12 deplo\ ed in a syno\ ial joint 150 The suture 122 exits from two points in the joint capsule 152 The ends of the suture 122 may be tied off together or separately This design offers the advantage of holding the depot J 20 up against the inside of the joint capsule \ 52 without rotating and potential!) interfering with motion of the joim 150
Several implant designs are contemplated for use in intervetebral disc and joint capsules that comprise bead-shaped depots stiung together along a suture Such an embodiment implant 160 ia depicted in FΪG. 16 Analogous Io the embodiments discussed earlier, the beads 164 may be in the form of a solid, biodegradable material, such as a polymer, loaded wiih a therapeutic agent, alternatively, the beads 164 may form a cavity that is packed with the therapeutic agent, and which may diffuse through the walls of the cavity. The beads 164 elute the therapeutic agent when disposed within the targeted tissue site. The beads 164 may be from about 100 μm to about 5 mm in diameter, it may be more preferable that the beads !64 range in size from about I mm to about 2 mm. The suture 162 may be either a degradable or a non-degradable material. Extending from an end of the implant 160 is an optional needle or barb 166 to serve as an anchoring device that retains the strand 160 within the targeted tissue site, such as a disc or joint capsule.
This implant 160 optimally positions the therapeutic agent eluting beads 164 along the route of inflamed tissue, resulting in a more effective distribution of the therapeutic agent and clinical effectiveness As shown in FlG. 17, the strand 160 may be implanted by inserting a cannula 170 containing the strand 160 of beads 164 as far as desired inside, for example, a disc, joint, or soft tissue, and then deploying the barb 166 into the soft tissue
{such as the annυlus) and slowly retracting the cannula 170, which will result in the implant 160 being pulled from the cannula 170 By fixing, for example, the leading edge of the implant 160, the anchoring device 166 retains the beads 164 at the location where the therapeutic agent is desired. FIGS. 18 and 19 illustrate the implant 160 being deployed in targeted tissue sites. A very small hole is made in an intervertebral disc 180 or in a joint capsule 192 with a blunt probe, through which a cannula is inserted to implant the string 160 of beads 164. For example, as shown in FIG. 18, the implant 160 may be deployed inside a disc 180, with the anchoring device 166 embedded within the annular fώrosus of the disc 180. The beads 164 may extend inside the disc 180, and then externally along the nerve root 182. As shown in FlG. 19, the implant 160 may be deployed transverse across a joint 190. resulting in a more uniform distribution of the therapeutic agent within the synovial cav ity 194 of the joint 190, The suture 162 at the ends of the implant 160 may be tied off to the joint capsule 192 to anchor the implant 160 within the joint 190.
The present invention provides another method for administering a therapeutic agent to a targeted tissue site. As shown in FlG 20, the targeted tissue site may be a spinal canal 200 or tissue surrounding the spinal canal 200, such as a disc 202 or a nerve root 204 The spinal cord 206 rims through the spinal canal 200, which is provided by the vertebrae 208. As discussed earlier, microspheres 209 encapsulating the desired therapeutic agent may be formed hi a known manner. These microspheres 209 may then be deployed into the spina! canal 200, such as by injecting a carrier containing the microspheres 209 into the spinal canal 200. The microspheres 209 then eluie the therapeutic agent into the spina! canal 200. The microspheres 209 may disperse to the surrounding tissue, such as the nerve root 204 or the disc 202 Alternatively, to provide therapeutic treatment primarily to the disc 202 alone, the therapeutic-containing microspheres 209 may be directly injected into the disc 202. As shown in FiG. 21, microspheres 219 loaded with a therapeutic agent may he injected into a synovial cavity 212 to treat a joint 210. A syringe or similar device may be used to deploy the microspheres 2 I 9 into the joint cavity 212.
Microspheres, much iike a fluid, may disperse relatively quickly, depending upon the surrounding tissue type, and hence disperse the therapeutic agent In some situations, this may be desirable; in others, it may be more desirable to keep trie therapeutic agent tightly constrained to a well-defined target site. The present invention contemplates the use of adherent gels to so constrain dispersal of the therapeutic agent. These gels may be deployed, for example, in a disc space, in a spinal canal, or in surrounding tissue, or in a joint space, such as a synovial cavity. In this embodiment the gel is an adherent and/or settabie gel in order to stay in place within a joint space.
In one embodiment, a depot comprises an adherent gel comprising a therapeutic agent that is evenly distributed throughout the gel. The gel may be of any suitable type, as previously indicated, and should be sufficiently viscous as to prevent the gel from migrating from the targeted delivery site once deployed; the gel should, in effect, "stick"' to the targeted tissue site. The gel may, for example, solidify upon contact with the targeted tissue or after deployment from a targeted delivery- system. 'The targeted delivery system may be, for example, a syringe, a catheter or any other suitable device. The targeted delivery system may inject or spray the gel into or on the targeted tissue site. 'The therapeutic agent may he mixed into the gel prior to the gel being deployed at the targeted tissue site. The gel may be biodegradable. For the non-settable gels, they may be sold pre- mixed and just delivered, but for the adherent and/or settabie gel. they may need to be two component delivery systems that mix the two components upon injection to activate a chemical process to cause them to stick or set up
FIG. 22 illustrates a gel 212, imbued with a therapeutic agent and deployed around a targeted tissue site, a nerve root 210. The gel 212, either viscous or solid once deployed, 40 keeps the therapeutic agent closely bound to the nerve root 210. thereby providing a therapeutically effective dosage of the therapeutic agent to the nerve root 210, with the dosage gradient rapidly falling off outside of the region of the gel 212 The therapeutic agent is therefore tightly targeted at the nerve root 210 Alternatively, rather than directly admixing the therapeutic agent into the gel, the present invention also contemplates dispersing microspheres within the gel, the microspheres loaded with the therapeutic agent In one embodiment, the microspheres provide for a sustained release of the therapeutic agent In yet another embodiment, the gel, which is biodegradable, prevents the microspheres from releasing the therapeutic agent, the microspheres thus do not release the therapeutic agent until they have been released from the gel This embodiment is depicted in FlG 23. which shows a gel 222 deployed around a nerve root 220, the targeted tissue site Dispersed within the gel 222 are a plurality of microspheres 226 that encapsulate the desired therapeutic agent Dashed line 227 indicates the original deployment region of the gel 222; solid line 225 indicates the current deployment region of the gel 222 due to degradation of the ge! 222.
Microspheres 226 are thus released from the gel 222. Certain of these microspheres 228 degrade once released from the gel 222, thus releasing the therapeutic agent.
It will be appreciated that a localized delivery device, such as a pump or the like, may he used to deliver the microspheres to the targeted tissue site Similarly , a pump may be used to deliver the present invention gel, either with or without microspheres, to the target site. Examples of localized delivery systems are presented in co-pending United States patent application number 1 1/091,348, which is incorporated herein by reference 'flie use of depot implants to deliver anti-inflammatory or anabolic compounds to intervertebral discs or articulating joints has not been previously disclosed Hie specific designs disclosed and contemplated in this invention provide a way to insert depot implants into discs or joint capsules with minimal tissue disruption and interfering with normal joint motion It also prevents the depots from migrating away from the inflamed tissue and allowing for more uniform distribution of the daig All publications cited in the specification, both patent publications and non-patent publications, are indicative of the level of skill of those skilled in the art to which this invention pertains All these publications are herein fully incorporated by reference to the same extent as if each individual publication were specifically and individually indicated as being incorporated by reference.
Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as defined by the following claims.

Claims

What is claimed is;
1 A drag depot implant comprising: a body, a therapeutic agent disposed in the body; and an anchoring system extending from the body, the anchoring system adapted to limit movement of the body from a targeted tissue; wherein the body is capable of eiuting the therapeutic agent.
2. The daig depot implant of claim I wherein the body is rod-shaped, and the anchoring system extends from the rod-shaped body and is adapted to limit translation^ movement of the body along a longitudinal axis of the rod-shaped body
3. The daig depot implant of claim 2 wherein the anchoring system is a barb
4. The drug depot implant of claim 3 wherein the barb is flexible.
5. The drug depot implant of claim 2 wherein the anchoring system provides a surface adapted to abut against a tissue plane.
6. The drug depot implant of claim 5 wherein the anchoring system is an end cap disposed on an end of the rod-shaped body.
7. The drug depot implant of claim 2 wherein the anchoring system is a suture.
8 The drug depot implant of claim 1 further comprising a radiographic marker adapted to assist in radiographic imaging of the drug depot implant.
9. The drug depot implant of claim 1 wherein the body comprises an active region within the body, the therapeutic agent disposed exclusively within the active region. 10, The drug depot implant of claim 1 wherein the body is formed from a solid, biodegradable material and the therapeutic agent is dispersed in at least a portion of the biodegradable material
1 1 , The drug depot implant of claim 10 further comprising a plurality of microspheres disposed in the biodegradable material, the microspheres encapsulating at least a portion of the therapeutic agent
S 2, The drug depot implant of claim 1 wherein the body comprises a shell that defines a cavity, the therapeutic agent disposed in the cavity, the shell at least partly permeable to the therapeutic agent
i 3 The drug depot implant of claim 1 wherein the daig depot implant provides an optimal concentration of the therapeutic agent from about 1 cm to about 5 cm from the drug depot implant.
14 The drug depot implant of claim 1 wherein the therapeutic agent is an antiinflammatory agent
15. A drug depot implant comprising a plurality of beads connected together by suture, the beads comprising a therapeutic agent.
i 6. The drug depot implant of claim 15 wherein the beads are each formed from a solid, biodegradable material, and the therapeutic agent is dispersed throughout the biodegradable material.
17. The drug depot implant of claim 15 wherein each bead comprises a shell that defines a cavity, the therapeutic agent is disposed within the cavity, the shell at least partly permeable to the therapeutic agent
1 S. The drug depot implant of claim 15 wherein an anchoring system is connected to the suture. S 9 The drug depot implant of claim 15 wherein the leading bead comprises an anchoring system
20 The drug depot implant of claim 18 w, herein the anchoring system is a hook or a barb
21 The drug depot implant of claim 18 w herein the beads are linearly disposed along the suture, and the anchoring system is attached to a leading end of the suture
22 The drug depot implant of claim 15 wherein the therapeutic agent is an anti- inflarømators agent
PCT/US2007/066496 2006-04-13 2007-04-12 Drug depot implant designs and methods of implantation WO2007121288A2 (en)

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Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008067234A2 (en) * 2006-11-28 2008-06-05 Warsaw Orthopedic, Inc Use of anti-cytokine agents for treating carpal and tarsal tunnel syndrome
WO2008157057A2 (en) * 2007-06-19 2008-12-24 Warsaw Orthopedic, Inc. Locally administrated low doses of corticosteroids
WO2009033046A1 (en) * 2007-09-05 2009-03-12 Warsaw Orthopedic, Inc. Apparatus for delivering treatment to a joint
EP2134409A1 (en) * 2007-03-09 2009-12-23 Anthem Orthopaedics, LLC Implantable medicament delivery device and delivery tool and method for use therewith
WO2010053786A2 (en) * 2008-10-29 2010-05-14 Warsaw Orthopedic, Inc. Drug depot delivery device and methods
WO2010059378A3 (en) * 2008-10-30 2010-08-12 Warsaw Orthopedic, Inc. Drug depot with anchor
WO2010051383A3 (en) * 2008-10-31 2010-08-26 Warsaw Orthopedic, Inc. A device and method for delivery of a drug depot
US7910123B2 (en) 2007-09-05 2011-03-22 Warsaw Orthopedic Methods of treating a trauma or disorder of the knee joint by local administration and sustained-delivery of a biological agent
EP2363122A1 (en) * 2006-07-26 2011-09-07 Medtronic, Inc. Clonidine to treat pain locally
CN102387833A (en) * 2009-03-20 2012-03-21 因卡伯实验室有限责任公司 Solid drug delivery apparatus, formulations and methods of use
US8202531B2 (en) 2008-07-23 2012-06-19 Warsaw Orthopedic, Inc. Drug depots having one or more anchoring members
US8557271B2 (en) 2008-07-16 2013-10-15 Warsaw Orthopedic, Inc. Drug depot implantable within a joint
US8877193B2 (en) 2003-05-13 2014-11-04 DePuy Synthes Products, LLC. Transdiscal administration of anti-TNFα antibodies and growth differentiation factors
US8986696B2 (en) 2007-12-21 2015-03-24 Depuy Mitek, Inc. Trans-capsular administration of p38 map kinase inhibitors into orthopedic joints
US10384048B2 (en) 2014-07-25 2019-08-20 Warsaw Orthopedic, Inc. Drug delivery device and methods having an occluding member
US10478603B2 (en) 2014-07-25 2019-11-19 Warsaw Orthopedic, Inc. Drug delivery device and methods having a retaining member
US10549081B2 (en) 2016-06-23 2020-02-04 Warsaw Orthopedic, Inc. Drug delivery device and methods having a retaining member
USRE49219E1 (en) 2003-11-26 2022-09-27 DePuy Synthes Products, Inc. Local intraosseous administration of bone forming agents and anti-resorptive agents, and devices therefor
US11478587B2 (en) 2016-11-08 2022-10-25 Warsaw Orthopedic, Inc. Drug depot delivery system and method
US11759614B2 (en) 2015-11-23 2023-09-19 Warsaw Orthopedic, Inc. Enhanced stylet for drug depot injector

Families Citing this family (615)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7115557B2 (en) 1998-09-25 2006-10-03 Sciaticon Ab Use of certain drugs for treating nerve root injury
JP4495589B2 (en) * 2002-08-27 2010-07-07 ウォーソー・オーソペディック・インコーポレーテッド System for intravertebral reduction
US20040229878A1 (en) * 2003-05-13 2004-11-18 Depuy Spine, Inc. Transdiscal administration of specific inhibitors of P38 kinase
US7429378B2 (en) * 2003-05-13 2008-09-30 Depuy Spine, Inc. Transdiscal administration of high affinity anti-MMP inhibitors
US8273347B2 (en) * 2003-05-13 2012-09-25 Depuy Spine, Inc. Autologous treatment of degenerated disc with cells
US20070084897A1 (en) 2003-05-20 2007-04-19 Shelton Frederick E Iv Articulating surgical stapling instrument incorporating a two-piece e-beam firing mechanism
US9060770B2 (en) 2003-05-20 2015-06-23 Ethicon Endo-Surgery, Inc. Robotically-driven surgical instrument with E-beam driver
US11890012B2 (en) 2004-07-28 2024-02-06 Cilag Gmbh International Staple cartridge comprising cartridge body and attached support
US8215531B2 (en) 2004-07-28 2012-07-10 Ethicon Endo-Surgery, Inc. Surgical stapling instrument having a medical substance dispenser
US20070194079A1 (en) 2005-08-31 2007-08-23 Hueil Joseph C Surgical stapling device with staple drivers of different height
US11246590B2 (en) 2005-08-31 2022-02-15 Cilag Gmbh International Staple cartridge including staple drivers having different unfired heights
US9237891B2 (en) 2005-08-31 2016-01-19 Ethicon Endo-Surgery, Inc. Robotically-controlled surgical stapling devices that produce formed staples having different lengths
US7934630B2 (en) 2005-08-31 2011-05-03 Ethicon Endo-Surgery, Inc. Staple cartridges for forming staples having differing formed staple heights
US11484312B2 (en) 2005-08-31 2022-11-01 Cilag Gmbh International Staple cartridge comprising a staple driver arrangement
US10159482B2 (en) 2005-08-31 2018-12-25 Ethicon Llc Fastener cartridge assembly comprising a fixed anvil and different staple heights
US7669746B2 (en) 2005-08-31 2010-03-02 Ethicon Endo-Surgery, Inc. Staple cartridges for forming staples having differing formed staple heights
US20070106317A1 (en) 2005-11-09 2007-05-10 Shelton Frederick E Iv Hydraulically and electrically actuated articulation joints for surgical instruments
US8820603B2 (en) 2006-01-31 2014-09-02 Ethicon Endo-Surgery, Inc. Accessing data stored in a memory of a surgical instrument
US20110006101A1 (en) 2009-02-06 2011-01-13 EthiconEndo-Surgery, Inc. Motor driven surgical fastener device with cutting member lockout arrangements
US20110290856A1 (en) 2006-01-31 2011-12-01 Ethicon Endo-Surgery, Inc. Robotically-controlled surgical instrument with force-feedback capabilities
US11793518B2 (en) 2006-01-31 2023-10-24 Cilag Gmbh International Powered surgical instruments with firing system lockout arrangements
US11278279B2 (en) 2006-01-31 2022-03-22 Cilag Gmbh International Surgical instrument assembly
US11224427B2 (en) 2006-01-31 2022-01-18 Cilag Gmbh International Surgical stapling system including a console and retraction assembly
US9861359B2 (en) 2006-01-31 2018-01-09 Ethicon Llc Powered surgical instruments with firing system lockout arrangements
US8708213B2 (en) 2006-01-31 2014-04-29 Ethicon Endo-Surgery, Inc. Surgical instrument having a feedback system
US20120292367A1 (en) 2006-01-31 2012-11-22 Ethicon Endo-Surgery, Inc. Robotically-controlled end effector
US7845537B2 (en) 2006-01-31 2010-12-07 Ethicon Endo-Surgery, Inc. Surgical instrument having recording capabilities
US8186555B2 (en) 2006-01-31 2012-05-29 Ethicon Endo-Surgery, Inc. Motor-driven surgical cutting and fastening instrument with mechanical closure system
US7753904B2 (en) 2006-01-31 2010-07-13 Ethicon Endo-Surgery, Inc. Endoscopic surgical instrument with a handle that can articulate with respect to the shaft
US20110024477A1 (en) 2009-02-06 2011-02-03 Hall Steven G Driven Surgical Stapler Improvements
US20070225562A1 (en) 2006-03-23 2007-09-27 Ethicon Endo-Surgery, Inc. Articulating endoscopic accessory channel
US8992422B2 (en) 2006-03-23 2015-03-31 Ethicon Endo-Surgery, Inc. Robotically-controlled endoscopic accessory channel
US7741273B2 (en) * 2006-04-13 2010-06-22 Warsaw Orthopedic, Inc. Drug depot implant designs
KR101649457B1 (en) 2006-04-25 2016-08-19 칠드런'즈 메디컬 센터 코포레이션 Methods and compositions for the treatment of open and closed wound spinal cord injuries
US9173732B2 (en) * 2006-04-25 2015-11-03 The Children's Medical Center Corporation Medical devices for use in the surgical treatment of hyperproliferative diseases affecting the spinal cord
US9474645B2 (en) * 2006-06-21 2016-10-25 Johnson & Johnson Vision Care, Inc. Punctal plugs for the delivery of active agents
US8322455B2 (en) 2006-06-27 2012-12-04 Ethicon Endo-Surgery, Inc. Manually driven surgical cutting and fastening instrument
US8138160B2 (en) 2006-08-03 2012-03-20 Warsaw Orthopedic, Inc. Reagents, methods and systems to suppress pro-inflammatory cytokines
US20080064626A1 (en) * 2006-09-08 2008-03-13 Zanella John M Methods of treating tendonitis in a subject by using an anti-cytokine agent
US7506791B2 (en) 2006-09-29 2009-03-24 Ethicon Endo-Surgery, Inc. Surgical stapling instrument with mechanical mechanism for limiting maximum tissue compression
US10130359B2 (en) 2006-09-29 2018-11-20 Ethicon Llc Method for forming a staple
US10568652B2 (en) 2006-09-29 2020-02-25 Ethicon Llc Surgical staples having attached drivers of different heights and stapling instruments for deploying the same
US20080119927A1 (en) * 2006-11-17 2008-05-22 Medtronic Vascular, Inc. Stent Coating Including Therapeutic Biodegradable Glass, and Method of Making
US8684253B2 (en) 2007-01-10 2014-04-01 Ethicon Endo-Surgery, Inc. Surgical instrument with wireless communication between a control unit of a robotic system and remote sensor
US11291441B2 (en) 2007-01-10 2022-04-05 Cilag Gmbh International Surgical instrument with wireless communication between control unit and remote sensor
US8652120B2 (en) 2007-01-10 2014-02-18 Ethicon Endo-Surgery, Inc. Surgical instrument with wireless communication between control unit and sensor transponders
US11039836B2 (en) 2007-01-11 2021-06-22 Cilag Gmbh International Staple cartridge for use with a surgical stapling instrument
US8540128B2 (en) 2007-01-11 2013-09-24 Ethicon Endo-Surgery, Inc. Surgical stapling device with a curved end effector
ES2402672T3 (en) * 2007-01-25 2013-05-07 Biopharm Gesellschaft Zur Biotechnologischen Entwicklung Von Pharmaka Mbh Use of GDF-5 for improvement or maintenance of dermal appearance
US8727197B2 (en) 2007-03-15 2014-05-20 Ethicon Endo-Surgery, Inc. Staple cartridge cavity configuration with cooperative surgical staple
US8893946B2 (en) 2007-03-28 2014-11-25 Ethicon Endo-Surgery, Inc. Laparoscopic tissue thickness and clamp load measuring devices
US20080255664A1 (en) * 2007-04-10 2008-10-16 Mdesign International Percutaneously deliverable orthopedic joint device
US11857181B2 (en) 2007-06-04 2024-01-02 Cilag Gmbh International Robotically-controlled shaft based rotary drive systems for surgical instruments
US8931682B2 (en) 2007-06-04 2015-01-13 Ethicon Endo-Surgery, Inc. Robotically-controlled shaft based rotary drive systems for surgical instruments
US7753245B2 (en) 2007-06-22 2010-07-13 Ethicon Endo-Surgery, Inc. Surgical stapling instruments
US8308040B2 (en) 2007-06-22 2012-11-13 Ethicon Endo-Surgery, Inc. Surgical stapling instrument with an articulatable end effector
US11849941B2 (en) 2007-06-29 2023-12-26 Cilag Gmbh International Staple cartridge having staple cavities extending at a transverse angle relative to a longitudinal cartridge axis
JP2010536430A (en) * 2007-08-15 2010-12-02 ウィルソン−クック・メディカル・インコーポレーテッド Soft stent deployment system
US8470360B2 (en) * 2008-04-18 2013-06-25 Warsaw Orthopedic, Inc. Drug depots having different release profiles for reducing, preventing or treating pain and inflammation
WO2009042841A2 (en) 2007-09-27 2009-04-02 Angiotech Pharmaceuticals, Inc. Self-retaining sutures including tissue retainers having improved strength
US20090110637A1 (en) * 2007-10-26 2009-04-30 Warsaw Orthopedic, Inc. LMP and Regulation of Tissue Growth
US20090162351A1 (en) * 2007-12-21 2009-06-25 Depuy Spine, Inc. Transdiscal administration of inhibitors of p38 MAP kinase
EP2240110A4 (en) * 2008-01-29 2015-07-01 Superdimension Ltd Target identification tool for intra body localization
WO2009100441A2 (en) * 2008-02-08 2009-08-13 Impax Laboratories, Inc. Depot formulations
US8561870B2 (en) 2008-02-13 2013-10-22 Ethicon Endo-Surgery, Inc. Surgical stapling instrument
BRPI0901282A2 (en) 2008-02-14 2009-11-17 Ethicon Endo Surgery Inc surgical cutting and fixation instrument with rf electrodes
US7819298B2 (en) 2008-02-14 2010-10-26 Ethicon Endo-Surgery, Inc. Surgical stapling apparatus with control features operable with one hand
US8657174B2 (en) 2008-02-14 2014-02-25 Ethicon Endo-Surgery, Inc. Motorized surgical cutting and fastening instrument having handle based power source
US8573465B2 (en) 2008-02-14 2013-11-05 Ethicon Endo-Surgery, Inc. Robotically-controlled surgical end effector system with rotary actuated closure systems
US9179912B2 (en) 2008-02-14 2015-11-10 Ethicon Endo-Surgery, Inc. Robotically-controlled motorized surgical cutting and fastening instrument
US7866527B2 (en) 2008-02-14 2011-01-11 Ethicon Endo-Surgery, Inc. Surgical stapling apparatus with interlockable firing system
US8636736B2 (en) 2008-02-14 2014-01-28 Ethicon Endo-Surgery, Inc. Motorized surgical cutting and fastening instrument
US8758391B2 (en) 2008-02-14 2014-06-24 Ethicon Endo-Surgery, Inc. Interchangeable tools for surgical instruments
US11272927B2 (en) 2008-02-15 2022-03-15 Cilag Gmbh International Layer arrangements for surgical staple cartridges
US9770245B2 (en) 2008-02-15 2017-09-26 Ethicon Llc Layer arrangements for surgical staple cartridges
US8828354B2 (en) * 2008-03-27 2014-09-09 Warsaw Orthopedic, Inc. Pharmaceutical gels and methods for delivering therapeutic agents to a site beneath the skin
US20090263443A1 (en) * 2008-04-18 2009-10-22 Warsaw Orthopedics, Inc. Methods for treating post-operative effects such as spasticity and shivering with clondine
US20090264489A1 (en) * 2008-04-18 2009-10-22 Warsaw Orthopedic, Inc. Method for Treating Acute Pain with a Formulated Drug Depot in Combination with a Liquid Formulation
US8889173B2 (en) * 2008-04-18 2014-11-18 Warsaw Orthopedic, Inc. Alpha adrenergic receptor agonists for treatment of pain and/or inflammation
US20090263451A1 (en) * 2008-04-18 2009-10-22 Warsaw Orthopedic, Inc. Anti-Inflammatory and/or Analgesic Agents for Treatment of Myofascial Pain
US9289409B2 (en) * 2008-04-18 2016-03-22 Warsaw Orthopedic, Inc. Sulindac formulations in a biodegradable material
US20090264477A1 (en) * 2008-04-18 2009-10-22 Warsaw Orthopedic, Inc., An Indiana Corporation Beta adrenergic receptor agonists for treatment of pain and/or inflammation
US20090264478A1 (en) * 2008-04-18 2009-10-22 Warsaw Orthopedic, Inc. Sulfasalazine formulations in a biodegradable polymer carrier
USRE48948E1 (en) 2008-04-18 2022-03-01 Warsaw Orthopedic, Inc. Clonidine compounds in a biodegradable polymer
US8956641B2 (en) 2008-04-18 2015-02-17 Warsaw Orthopedic, Inc. Alpha adrenergic receptor agonists for treatment of inflammatory diseases
US8629172B2 (en) 2008-04-18 2014-01-14 Warsaw Orthopedic, Inc. Methods and compositions for treating post-operative pain comprising clonidine
US8420114B2 (en) * 2008-04-18 2013-04-16 Warsaw Orthopedic, Inc. Alpha and beta adrenergic receptor agonists for treatment of pain and / or inflammation
US8883768B2 (en) * 2008-04-18 2014-11-11 Warsaw Orthopedic, Inc. Fluocinolone implants to protect against undesirable bone and cartilage destruction
US8956636B2 (en) 2008-04-18 2015-02-17 Warsaw Orthopedic, Inc. Methods and compositions for treating postoperative pain comprosing ketorolac
US9125917B2 (en) * 2008-04-18 2015-09-08 Warsaw Orthopedic, Inc. Fluocinolone formulations in a biodegradable polymer carrier
US9132085B2 (en) 2008-04-18 2015-09-15 Warsaw Orthopedic, Inc. Compositions and methods for treating post-operative pain using clonidine and bupivacaine
US9132119B2 (en) 2008-04-18 2015-09-15 Medtronic, Inc. Clonidine formulation in a polyorthoester carrier
US8722079B2 (en) 2008-04-18 2014-05-13 Warsaw Orthopedic, Inc. Methods for treating conditions such as dystonia and post-stroke spasticity with clonidine
US20090263489A1 (en) * 2008-04-18 2009-10-22 Warsaw Orthopedic, Inc. Analgesic and anti-inflammatory compositions and methods for reducing, preventing or treating pain and inflammation
US8846068B2 (en) 2008-04-18 2014-09-30 Warsaw Orthopedic, Inc. Methods and compositions for treating post-operative pain comprising a local anesthetic
US9072727B2 (en) * 2008-04-18 2015-07-07 Warsaw Orthopedic, Inc. Alpha adrenergic receptor agonists for treatment of degenerative disc disease
US8557273B2 (en) 2008-04-18 2013-10-15 Medtronic, Inc. Medical devices and methods including polymers having biologically active agents therein
US20090264906A1 (en) * 2008-04-22 2009-10-22 Medtronic Vascular, Inc. Cuff Device
US20090299330A1 (en) * 2008-04-28 2009-12-03 Mac Iver Robroy H Cellular Delivery Device
US20100015049A1 (en) * 2008-07-16 2010-01-21 Warsaw Orthopedic, Inc. Methods and compositions for treating postoperative pain comprising nonsteroidal anti-inflammatory agents
US9492375B2 (en) 2008-07-23 2016-11-15 Warsaw Orthopedic, Inc. Foam carrier for bone grafting
AU2008360388A1 (en) * 2008-08-05 2010-02-11 Children's Medical Center Corporation Medical devices for use in the surgical treatment of hyperproliferative diseases affecting the spinal cord
US9700431B2 (en) 2008-08-13 2017-07-11 Smed-Ta/Td, Llc Orthopaedic implant with porous structural member
US9616205B2 (en) 2008-08-13 2017-04-11 Smed-Ta/Td, Llc Drug delivery implants
US10842645B2 (en) 2008-08-13 2020-11-24 Smed-Ta/Td, Llc Orthopaedic implant with porous structural member
US20100042213A1 (en) 2008-08-13 2010-02-18 Nebosky Paul S Drug delivery implants
WO2010019788A1 (en) 2008-08-13 2010-02-18 Smed-Ta/Td. Llc Drug delivery implants
WO2010025386A1 (en) 2008-08-29 2010-03-04 Smed-Ta/Td, Llc Orthopaedic implant
PL3476312T3 (en) 2008-09-19 2024-03-11 Ethicon Llc Surgical stapler with apparatus for adjusting staple height
US7857186B2 (en) 2008-09-19 2010-12-28 Ethicon Endo-Surgery, Inc. Surgical stapler having an intermediate closing position
US8210411B2 (en) 2008-09-23 2012-07-03 Ethicon Endo-Surgery, Inc. Motor-driven surgical cutting instrument
US9005230B2 (en) 2008-09-23 2015-04-14 Ethicon Endo-Surgery, Inc. Motorized surgical instrument
US9386983B2 (en) 2008-09-23 2016-07-12 Ethicon Endo-Surgery, Llc Robotically-controlled motorized surgical instrument
US11648005B2 (en) 2008-09-23 2023-05-16 Cilag Gmbh International Robotically-controlled motorized surgical instrument with an end effector
US8608045B2 (en) 2008-10-10 2013-12-17 Ethicon Endo-Sugery, Inc. Powered surgical cutting and stapling apparatus with manually retractable firing system
US20100098746A1 (en) * 2008-10-20 2010-04-22 Warsaw Orthopedic, Inc. Compositions and methods for treating periodontal disease comprising clonidine, sulindac and/or fluocinolone
US9161903B2 (en) 2008-10-31 2015-10-20 Warsaw Orthopedic, Inc. Flowable composition that hardens on delivery to a target tissue site beneath the skin
ES2572368T5 (en) 2008-12-22 2021-12-16 Univ Melbourne Treatment of osteoarthritis
EP2387418B1 (en) * 2008-12-22 2018-06-13 The University of Melbourne Pain treatment
US8980317B2 (en) 2008-12-23 2015-03-17 Warsaw Orthopedic, Inc. Methods and compositions for treating infections comprising a local anesthetic
US8517239B2 (en) 2009-02-05 2013-08-27 Ethicon Endo-Surgery, Inc. Surgical stapling instrument comprising a magnetic element driver
CN102341048A (en) 2009-02-06 2012-02-01 伊西康内外科公司 Driven surgical stapler improvements
US8444036B2 (en) 2009-02-06 2013-05-21 Ethicon Endo-Surgery, Inc. Motor driven surgical fastener device with mechanisms for adjusting a tissue gap within the end effector
DK2393927T3 (en) 2009-02-09 2015-03-30 Morphosys Ag Preparation of oligoclonal mixtures of antibodies in the individual cells
US20100228097A1 (en) * 2009-03-04 2010-09-09 Warsaw Orthopedic, Inc. Methods and compositions to diagnose pain
US20100226959A1 (en) * 2009-03-04 2010-09-09 Warsaw Orthopedic, Inc. Matrix that prolongs growth factor release
US20100239632A1 (en) * 2009-03-23 2010-09-23 Warsaw Orthopedic, Inc. Drug depots for treatment of pain and inflammation in sinus and nasal cavities or cardiac tissue
EP2756799B1 (en) * 2009-06-26 2016-04-20 Cianna Medical, Inc. System for localizing markers or tissue structures within a body
US9386942B2 (en) 2009-06-26 2016-07-12 Cianna Medical, Inc. Apparatus, systems, and methods for localizing markers or tissue structures within a body
US8617583B2 (en) 2009-07-17 2013-12-31 Warsaw Orthopedic, Inc. Alpha adrenergic receptor agonists for prevention or treatment of a hematoma, edema, and/or deep vein thrombosis
US8231891B2 (en) 2009-07-31 2012-07-31 Warsaw Orthopedic, Inc. Implantable drug depot for weight control
US20110097375A1 (en) 2009-10-26 2011-04-28 Warsaw Orthopedic, Inc. Formulation for preventing or reducing bleeding at a surgical site
US20110097380A1 (en) * 2009-10-28 2011-04-28 Warsaw Orthopedic, Inc. Clonidine formulations having antimicrobial properties
US9504698B2 (en) * 2009-10-29 2016-11-29 Warsaw Orthopedic, Inc. Flowable composition that sets to a substantially non-flowable state
US8597192B2 (en) 2009-10-30 2013-12-03 Warsaw Orthopedic, Inc. Ultrasonic devices and methods to diagnose pain generators
US20110106110A1 (en) * 2009-10-30 2011-05-05 Warsaw Orthopedic, Inc. Devices and methods for implanting a plurality of drug depots having one or more anchoring members
US8851354B2 (en) 2009-12-24 2014-10-07 Ethicon Endo-Surgery, Inc. Surgical cutting instrument that analyzes tissue thickness
US8220688B2 (en) 2009-12-24 2012-07-17 Ethicon Endo-Surgery, Inc. Motor-driven surgical cutting instrument with electric actuator directional control assembly
US8475824B2 (en) * 2010-01-26 2013-07-02 Warsaw Orthopedic, Inc. Resorbable matrix having elongated particles
US8758791B2 (en) 2010-01-26 2014-06-24 Warsaw Orthopedic, Inc. Highly compression resistant matrix with porous skeleton
US9486500B2 (en) 2010-01-28 2016-11-08 Warsaw Orthopedic, Inc. Osteoimplant and methods for making
US9125902B2 (en) * 2010-01-28 2015-09-08 Warsaw Orthopedic, Inc. Methods for treating an intervertebral disc using local analgesics
US9050274B2 (en) * 2010-01-28 2015-06-09 Warsaw Orthopedic, Inc. Compositions and methods for treating an intervertebral disc using bulking agents or sealing agents
WO2011106502A2 (en) * 2010-02-25 2011-09-01 Mayo Foundation For Medical Education And Research Delivering drugs to desired locations within a mammal
US8685024B2 (en) 2010-04-14 2014-04-01 Arrowhead Medical Device Technologies, Llc Intramedullary fixation device and methods for bone fixation and stabilization
US10349987B2 (en) 2010-04-14 2019-07-16 Arrowhead Medical Device Technologies, Llc Intramedullary fixation devices
CA2798373C (en) 2010-05-04 2018-10-23 Ethicon, Llc Self-retaining systems having laser-cut retainers
GB2480295A (en) * 2010-05-12 2011-11-16 Alan John Waddon Polymeric aqueous composition
US8716204B2 (en) 2010-07-27 2014-05-06 Zimmer, Inc. Synthetic synovial fluid compositions and methods for making the same
US8783543B2 (en) 2010-07-30 2014-07-22 Ethicon Endo-Surgery, Inc. Tissue acquisition arrangements and methods for surgical stapling devices
US10420923B1 (en) 2010-08-10 2019-09-24 Amiram Katz Method and device for intrathecal administering of immunoglobulin
US8246571B2 (en) 2010-08-24 2012-08-21 Warsaw Orthopedic, Inc. Drug storage and delivery device having a retaining member
US11298125B2 (en) 2010-09-30 2022-04-12 Cilag Gmbh International Tissue stapler having a thickness compensator
US9314246B2 (en) 2010-09-30 2016-04-19 Ethicon Endo-Surgery, Llc Tissue stapler having a thickness compensator incorporating an anti-inflammatory agent
US9517063B2 (en) * 2012-03-28 2016-12-13 Ethicon Endo-Surgery, Llc Movable member for use with a tissue thickness compensator
WO2012042026A1 (en) 2010-09-30 2012-04-05 Ablynx Nv Biological materials related to c-met
US11812965B2 (en) 2010-09-30 2023-11-14 Cilag Gmbh International Layer of material for a surgical end effector
US11644471B2 (en) * 2010-09-30 2023-05-09 Ablynx N.V. Techniques for predicting, detecting and reducing aspecific protein interference in assays involving immunoglobulin single variable domains
US11849952B2 (en) 2010-09-30 2023-12-26 Cilag Gmbh International Staple cartridge comprising staples positioned within a compressible portion thereof
US9332974B2 (en) 2010-09-30 2016-05-10 Ethicon Endo-Surgery, Llc Layered tissue thickness compensator
US9204880B2 (en) 2012-03-28 2015-12-08 Ethicon Endo-Surgery, Inc. Tissue thickness compensator comprising capsules defining a low pressure environment
US10945731B2 (en) 2010-09-30 2021-03-16 Ethicon Llc Tissue thickness compensator comprising controlled release and expansion
US9364233B2 (en) 2010-09-30 2016-06-14 Ethicon Endo-Surgery, Llc Tissue thickness compensators for circular surgical staplers
US9055941B2 (en) 2011-09-23 2015-06-16 Ethicon Endo-Surgery, Inc. Staple cartridge including collapsible deck
US9016542B2 (en) 2010-09-30 2015-04-28 Ethicon Endo-Surgery, Inc. Staple cartridge comprising compressible distortion resistant components
EP2621356B1 (en) 2010-09-30 2018-03-07 Ethicon LLC Fastener system comprising a retention matrix and an alignment matrix
US9386988B2 (en) 2010-09-30 2016-07-12 Ethicon End-Surgery, LLC Retainer assembly including a tissue thickness compensator
US9220501B2 (en) 2010-09-30 2015-12-29 Ethicon Endo-Surgery, Inc. Tissue thickness compensators
US9629814B2 (en) 2010-09-30 2017-04-25 Ethicon Endo-Surgery, Llc Tissue thickness compensator configured to redistribute compressive forces
US9282962B2 (en) 2010-09-30 2016-03-15 Ethicon Endo-Surgery, Llc Adhesive film laminate
US9433419B2 (en) 2010-09-30 2016-09-06 Ethicon Endo-Surgery, Inc. Tissue thickness compensator comprising a plurality of layers
US9307989B2 (en) 2012-03-28 2016-04-12 Ethicon Endo-Surgery, Llc Tissue stapler having a thickness compensator incorportating a hydrophobic agent
US9211120B2 (en) 2011-04-29 2015-12-15 Ethicon Endo-Surgery, Inc. Tissue thickness compensator comprising a plurality of medicaments
US8695866B2 (en) 2010-10-01 2014-04-15 Ethicon Endo-Surgery, Inc. Surgical instrument having a power control circuit
US8900616B2 (en) 2010-10-22 2014-12-02 Covidien Lp System and method for satellite drug delivery
WO2012054815A1 (en) 2010-10-22 2012-04-26 Duke University Slow-release formulations of 5-hydroxytryptophan as an adjunct to pro-serotonergic therapies
US8740982B2 (en) 2010-10-26 2014-06-03 Kyphon Sarl Devices containing a chemonucleolysis agent and methods for treating an intervertebral disc or spinal arachnoiditis
US8404268B2 (en) 2010-10-26 2013-03-26 Kyphon Sarl Locally targeted anti-fibrotic agents and methods of use
US9414930B2 (en) 2010-10-26 2016-08-16 Kyphon SÀRL Activatable devices containing a chemonucleolysis agent
WO2012061658A2 (en) * 2010-11-03 2012-05-10 Angiotech Pharmaceuticals, Inc. Drug-eluting self-retaining sutures and methods relating thereto
US9675341B2 (en) 2010-11-09 2017-06-13 Ethicon Inc. Emergency self-retaining sutures and packaging
WO2012075440A2 (en) * 2010-12-03 2012-06-07 Warsaw Orthopedic, Inc. Compositions and methods for delivering clonidine to a target tissue site
WO2012075451A2 (en) 2010-12-03 2012-06-07 Warsaw Orthopedic, Inc. Clonidine and gaba compounds in a biodegradable polymer carrier
WO2012075447A2 (en) 2010-12-03 2012-06-07 Warsaw Orthopedic, Inc. Compositions and methods for delivering clonidine and bupivacaine to a target tissue site
US9060978B2 (en) * 2011-01-24 2015-06-23 Warsaw Orthopedic, Inc. Method for treating an intervertebral disc disorder by administering a dominant negative tumor necrosis factor antagonist
US9717779B2 (en) 2011-01-31 2017-08-01 Warsaw Orthopedic, Inc. Implantable matrix having optimum ligand concentrations
US8870845B2 (en) * 2011-02-10 2014-10-28 Terumo Kabushiki Kaisha Method for alleviating condition of spinal canal stenosis by local administration of medicine
AU2012220564A1 (en) * 2011-02-23 2013-08-29 Ams Research Corporation Drug releasing pelvic treatment system and method
WO2012121451A1 (en) * 2011-03-08 2012-09-13 연세대학교 산학협력단 Method for inducing in vivo migration of stem cell
US9511077B2 (en) 2011-04-25 2016-12-06 Warsaw Orthopedic, Inc. Medical devices and methods comprising an anabolic agent for wound healing
US9592243B2 (en) 2011-04-25 2017-03-14 Warsaw Orthopedic, Inc. Medical devices and methods comprising an anabolic agent for treatment of an injury
CA2834649C (en) 2011-04-29 2021-02-16 Ethicon Endo-Surgery, Inc. Staple cartridge comprising staples positioned within a compressible portion thereof
US11207064B2 (en) 2011-05-27 2021-12-28 Cilag Gmbh International Automated end effector component reloading system for use with a robotic system
US9072535B2 (en) 2011-05-27 2015-07-07 Ethicon Endo-Surgery, Inc. Surgical stapling instruments with rotatable staple deployment arrangements
US20130172931A1 (en) 2011-06-06 2013-07-04 Jeffrey M. Gross Methods and devices for soft palate tissue elevation procedures
CN103889434B (en) 2011-06-21 2017-02-15 Bvw控股公司 Medical device comprising boswellic acid
CN108653728B (en) 2011-06-23 2022-11-18 埃博灵克斯股份有限公司 Techniques for predicting, detecting, and reducing non-specific protein interference in assays involving immunoglobulin single variable domains
PT2723771T (en) 2011-06-23 2019-12-11 Ablynx Nv Serum albumin binding proteins
WO2013003885A2 (en) * 2011-07-01 2013-01-10 David Noble Intraosseous infusion device
US9205241B2 (en) 2011-07-12 2015-12-08 Warsaw Orthopedic, Inc. Medical devices and methods comprising an adhesive material
US9132194B2 (en) 2011-07-12 2015-09-15 Warsaw Orthopedic, Inc. Medical devices and methods comprising an adhesive sheet containing a drug depot
US9050084B2 (en) 2011-09-23 2015-06-09 Ethicon Endo-Surgery, Inc. Staple cartridge including collapsible deck arrangement
US9346884B2 (en) 2011-09-30 2016-05-24 Ablynx N.V. Biological materials related to c-Met
US8685106B2 (en) * 2011-11-15 2014-04-01 Abraham Lin Method of a pharmaceutical delivery system for use within a joint replacement
US8758806B2 (en) * 2012-01-23 2014-06-24 Warsaw Orthopedic, Inc. Human lubrication gel
US9044230B2 (en) 2012-02-13 2015-06-02 Ethicon Endo-Surgery, Inc. Surgical cutting and fastening instrument with apparatus for determining cartridge and firing motion status
BR112014024102B1 (en) 2012-03-28 2022-03-03 Ethicon Endo-Surgery, Inc CLAMP CARTRIDGE ASSEMBLY FOR A SURGICAL INSTRUMENT AND END ACTUATOR ASSEMBLY FOR A SURGICAL INSTRUMENT
CN104379068B (en) 2012-03-28 2017-09-22 伊西康内外科公司 Holding device assembly including tissue thickness compensation part
BR112014024098B1 (en) 2012-03-28 2021-05-25 Ethicon Endo-Surgery, Inc. staple cartridge
US9511018B2 (en) 2012-04-05 2016-12-06 Warsaw Orthopedic, Inc. Clonidine compounds in a biodegradable matrix
US8735504B2 (en) 2012-05-02 2014-05-27 Warsaw Orthopedic, Inc. Methods for preparing polymers having low residual monomer content
US9101358B2 (en) 2012-06-15 2015-08-11 Ethicon Endo-Surgery, Inc. Articulatable surgical instrument comprising a firing drive
US9381326B2 (en) * 2012-06-15 2016-07-05 W. L. Gore & Associates, Inc. Vascular occlusion and drug delivery devices, systems, and methods
US9282974B2 (en) 2012-06-28 2016-03-15 Ethicon Endo-Surgery, Llc Empty clip cartridge lockout
US9226751B2 (en) 2012-06-28 2016-01-05 Ethicon Endo-Surgery, Inc. Surgical instrument system including replaceable end effectors
US11278284B2 (en) 2012-06-28 2022-03-22 Cilag Gmbh International Rotary drive arrangements for surgical instruments
JP6290201B2 (en) 2012-06-28 2018-03-07 エシコン・エンド−サージェリィ・インコーポレイテッドＥｔｈｉｃｏｎ Ｅｎｄｏ−Ｓｕｒｇｅｒｙ，Ｉｎｃ． Lockout for empty clip cartridge
BR112014032776B1 (en) 2012-06-28 2021-09-08 Ethicon Endo-Surgery, Inc SURGICAL INSTRUMENT SYSTEM AND SURGICAL KIT FOR USE WITH A SURGICAL INSTRUMENT SYSTEM
US9204879B2 (en) 2012-06-28 2015-12-08 Ethicon Endo-Surgery, Inc. Flexible drive member
US20140001231A1 (en) 2012-06-28 2014-01-02 Ethicon Endo-Surgery, Inc. Firing system lockout arrangements for surgical instruments
US9289256B2 (en) 2012-06-28 2016-03-22 Ethicon Endo-Surgery, Llc Surgical end effectors having angled tissue-contacting surfaces
US9205204B2 (en) 2012-08-06 2015-12-08 Elwha Llc Devices and methods for wearable injection guides
US9550029B2 (en) 2012-10-30 2017-01-24 Elwha Llc Systems and methods for guiding injections
US10046119B2 (en) 2012-10-30 2018-08-14 Elwha Llc Systems and methods for generating an injection guide
AU2013362134B2 (en) * 2012-12-21 2018-07-05 Sykehuset Sorlandet Hf EGFR targeted therapy of neurological disorders and pain
US9066853B2 (en) 2013-01-15 2015-06-30 Warsaw Orthopedic, Inc. Clonidine compounds in a biodegradable fiber
US8945872B2 (en) 2013-01-25 2015-02-03 Warsaw Orthopedic, Inc. Methods of purifying human recombinant growth and differentiation factor-5 (rhGDF-5) protein
US8956829B2 (en) 2013-01-25 2015-02-17 Warsaw Orthopedic, Inc. Human recombinant growth and differentiaton factor-5 (rhGDF-5)
US9051389B2 (en) 2013-01-25 2015-06-09 Warsaw Orthopedic, Inc. Expression conditions and methods of human recombinant growth and differentiation factor-5 (rhGDF-5)
US9169308B2 (en) 2013-01-25 2015-10-27 Warsaw Orthopedic, Inc. Methods and compositions of human recombinant growth and differentiation factor-5 (rhGDF-5) isolated from inclusion bodies
US9359417B2 (en) 2013-01-25 2016-06-07 Warsaw Orthopedic, Inc. Cell cultures and methods of human recombinant growth and differentiaton factor-5 (rhGDF-5)
US9713437B2 (en) 2013-01-26 2017-07-25 Cianna Medical, Inc. Microwave antenna apparatus, systems, and methods for localizing markers or tissue structures within a body
US10660542B2 (en) 2013-01-26 2020-05-26 Cianna Medical, Inc. RFID markers and systems and methods for identifying and locating them
JP6382235B2 (en) 2013-03-01 2018-08-29 エシコン・エンド−サージェリィ・インコーポレイテッドＥｔｈｉｃｏｎ Ｅｎｄｏ−Ｓｕｒｇｅｒｙ，Ｉｎｃ． Articulatable surgical instrument with a conductive path for signal communication
US20140246475A1 (en) 2013-03-01 2014-09-04 Ethicon Endo-Surgery, Inc. Control methods for surgical instruments with removable implement portions
JP6345707B2 (en) 2013-03-01 2018-06-20 エシコン・エンド−サージェリィ・インコーポレイテッドＥｔｈｉｃｏｎ Ｅｎｄｏ−Ｓｕｒｇｅｒｙ，Ｉｎｃ． Surgical instrument with soft stop
EP2967687B1 (en) 2013-03-13 2019-01-09 Arrowhead Medical Device Technologies LLC Methods and implants for treating hammertoe and other deformities
US9452002B2 (en) 2013-03-13 2016-09-27 Arrowhead Medical Device Technologies, Llc Hammertoe implant with enhanced gripping surfaces
US20140263552A1 (en) 2013-03-13 2014-09-18 Ethicon Endo-Surgery, Inc. Staple cartridge tissue thickness sensor system
US9974580B2 (en) 2013-03-13 2018-05-22 Arrowhead Medical Device Technologies Llc Hammertoe implant with asymmetrical head
US9629629B2 (en) 2013-03-14 2017-04-25 Ethicon Endo-Surgey, LLC Control systems for surgical instruments
US9332987B2 (en) 2013-03-14 2016-05-10 Ethicon Endo-Surgery, Llc Control arrangements for a drive member of a surgical instrument
CA2907082C (en) 2013-03-15 2021-05-04 Brigham Young University Methods for treating inflammation, autoimmune disorders and pain
US11524015B2 (en) 2013-03-15 2022-12-13 Brigham Young University Methods for treating inflammation, autoimmune disorders and pain
US9572577B2 (en) 2013-03-27 2017-02-21 Ethicon Endo-Surgery, Llc Fastener cartridge comprising a tissue thickness compensator including openings therein
US9332984B2 (en) 2013-03-27 2016-05-10 Ethicon Endo-Surgery, Llc Fastener cartridge assemblies
US9795384B2 (en) 2013-03-27 2017-10-24 Ethicon Llc Fastener cartridge comprising a tissue thickness compensator and a gap setting element
BR112015026109B1 (en) 2013-04-16 2022-02-22 Ethicon Endo-Surgery, Inc surgical instrument
US9844368B2 (en) 2013-04-16 2017-12-19 Ethicon Llc Surgical system comprising first and second drive systems
GB201307262D0 (en) * 2013-04-23 2013-05-29 Chowdhury Dewan F H Device for containment and release of drug formulation
US9877727B2 (en) * 2013-05-02 2018-01-30 Empire Technology Development Llc Diverticulum treating device
US9574644B2 (en) 2013-05-30 2017-02-21 Ethicon Endo-Surgery, Llc Power module for use with a surgical instrument
US20150053746A1 (en) 2013-08-23 2015-02-26 Ethicon Endo-Surgery, Inc. Torque optimization for surgical instruments
JP6416260B2 (en) 2013-08-23 2018-10-31 エシコン エルエルシー Firing member retractor for a powered surgical instrument
GB201317641D0 (en) 2013-10-05 2013-11-20 Chowdhury Dewan F H Novel solid dosage form
US11690855B2 (en) 2013-10-17 2023-07-04 Brigham Young University Methods for treating lung infections and inflammation
US9968354B2 (en) 2013-12-23 2018-05-15 Ethicon Llc Surgical staples and methods for making the same
US9724092B2 (en) 2013-12-23 2017-08-08 Ethicon Llc Modular surgical instruments
US9839428B2 (en) 2013-12-23 2017-12-12 Ethicon Llc Surgical cutting and stapling instruments with independent jaw control features
US20150173756A1 (en) 2013-12-23 2015-06-25 Ethicon Endo-Surgery, Inc. Surgical cutting and stapling methods
US20150203527A1 (en) 2014-01-23 2015-07-23 Brigham Young University Cationic steroidal antimicrobials
US9962161B2 (en) 2014-02-12 2018-05-08 Ethicon Llc Deliverable surgical instrument
CN106232029B (en) 2014-02-24 2019-04-12 伊西康内外科有限责任公司 Fastening system including firing member locking piece
US9839422B2 (en) 2014-02-24 2017-12-12 Ethicon Llc Implantable layers and methods for altering implantable layers for use with surgical fastening instruments
US10201364B2 (en) 2014-03-26 2019-02-12 Ethicon Llc Surgical instrument comprising a rotatable shaft
US9733663B2 (en) 2014-03-26 2017-08-15 Ethicon Llc Power management through segmented circuit and variable voltage protection
BR112016021943B1 (en) 2014-03-26 2022-06-14 Ethicon Endo-Surgery, Llc SURGICAL INSTRUMENT FOR USE BY AN OPERATOR IN A SURGICAL PROCEDURE
US10004497B2 (en) 2014-03-26 2018-06-26 Ethicon Llc Interface systems for use with surgical instruments
US9913642B2 (en) 2014-03-26 2018-03-13 Ethicon Llc Surgical instrument comprising a sensor system
US10327764B2 (en) 2014-09-26 2019-06-25 Ethicon Llc Method for creating a flexible staple line
US10561422B2 (en) 2014-04-16 2020-02-18 Ethicon Llc Fastener cartridge comprising deployable tissue engaging members
BR112016023825B1 (en) 2014-04-16 2022-08-02 Ethicon Endo-Surgery, Llc STAPLE CARTRIDGE FOR USE WITH A SURGICAL STAPLER AND STAPLE CARTRIDGE FOR USE WITH A SURGICAL INSTRUMENT
JP6532889B2 (en) 2014-04-16 2019-06-19 エシコン エルエルシーＥｔｈｉｃｏｎ ＬＬＣ Fastener cartridge assembly and staple holder cover arrangement
US20150297223A1 (en) 2014-04-16 2015-10-22 Ethicon Endo-Surgery, Inc. Fastener cartridges including extensions having different configurations
JP6636452B2 (en) 2014-04-16 2020-01-29 エシコン エルエルシーＥｔｈｉｃｏｎ ＬＬＣ Fastener cartridge including extension having different configurations
US10045781B2 (en) 2014-06-13 2018-08-14 Ethicon Llc Closure lockout systems for surgical instruments
US11311294B2 (en) 2014-09-05 2022-04-26 Cilag Gmbh International Powered medical device including measurement of closure state of jaws
BR112017004361B1 (en) 2014-09-05 2023-04-11 Ethicon Llc ELECTRONIC SYSTEM FOR A SURGICAL INSTRUMENT
US10111679B2 (en) 2014-09-05 2018-10-30 Ethicon Llc Circuitry and sensors for powered medical device
US10105142B2 (en) 2014-09-18 2018-10-23 Ethicon Llc Surgical stapler with plurality of cutting elements
JP6819908B2 (en) * 2014-09-19 2021-01-27 オクラー リミテッド Ophthalmic pharmaceutical composition
US11523821B2 (en) 2014-09-26 2022-12-13 Cilag Gmbh International Method for creating a flexible staple line
JP6648119B2 (en) 2014-09-26 2020-02-14 エシコン エルエルシーＥｔｈｉｃｏｎ ＬＬＣ Surgical stapling buttress and accessory materials
US10076325B2 (en) 2014-10-13 2018-09-18 Ethicon Llc Surgical stapling apparatus comprising a tissue stop
US9924944B2 (en) 2014-10-16 2018-03-27 Ethicon Llc Staple cartridge comprising an adjunct material
FR3027232A1 (en) * 2014-10-20 2016-04-22 Melissa Estelle Berthelot DEVICE FOR PALLIATION DYNAMIC TO COGNITIVE DEFICITS
US10517594B2 (en) 2014-10-29 2019-12-31 Ethicon Llc Cartridge assemblies for surgical staplers
US11141153B2 (en) 2014-10-29 2021-10-12 Cilag Gmbh International Staple cartridges comprising driver arrangements
US9844376B2 (en) 2014-11-06 2017-12-19 Ethicon Llc Staple cartridge comprising a releasable adjunct material
US10736636B2 (en) 2014-12-10 2020-08-11 Ethicon Llc Articulatable surgical instrument system
US9844374B2 (en) 2014-12-18 2017-12-19 Ethicon Llc Surgical instrument systems comprising an articulatable end effector and means for adjusting the firing stroke of a firing member
US9987000B2 (en) 2014-12-18 2018-06-05 Ethicon Llc Surgical instrument assembly comprising a flexible articulation system
US10117649B2 (en) 2014-12-18 2018-11-06 Ethicon Llc Surgical instrument assembly comprising a lockable articulation system
US9844375B2 (en) 2014-12-18 2017-12-19 Ethicon Llc Drive arrangements for articulatable surgical instruments
US10188385B2 (en) 2014-12-18 2019-01-29 Ethicon Llc Surgical instrument system comprising lockable systems
MX2017008108A (en) 2014-12-18 2018-03-06 Ethicon Llc Surgical instrument with an anvil that is selectively movable about a discrete non-movable axis relative to a staple cartridge.
US10004501B2 (en) 2014-12-18 2018-06-26 Ethicon Llc Surgical instruments with improved closure arrangements
US10085748B2 (en) 2014-12-18 2018-10-02 Ethicon Llc Locking arrangements for detachable shaft assemblies with articulatable surgical end effectors
US10321907B2 (en) 2015-02-27 2019-06-18 Ethicon Llc System for monitoring whether a surgical instrument needs to be serviced
US9993258B2 (en) 2015-02-27 2018-06-12 Ethicon Llc Adaptable surgical instrument handle
US11154301B2 (en) 2015-02-27 2021-10-26 Cilag Gmbh International Modular stapling assembly
US10180463B2 (en) 2015-02-27 2019-01-15 Ethicon Llc Surgical apparatus configured to assess whether a performance parameter of the surgical apparatus is within an acceptable performance band
US10617412B2 (en) 2015-03-06 2020-04-14 Ethicon Llc System for detecting the mis-insertion of a staple cartridge into a surgical stapler
US10441279B2 (en) 2015-03-06 2019-10-15 Ethicon Llc Multiple level thresholds to modify operation of powered surgical instruments
JP2020121162A (en) 2015-03-06 2020-08-13 エシコン エルエルシーＥｔｈｉｃｏｎ ＬＬＣ Time dependent evaluation of sensor data to determine stability element, creep element and viscoelastic element of measurement
US10245033B2 (en) 2015-03-06 2019-04-02 Ethicon Llc Surgical instrument comprising a lockable battery housing
US9924961B2 (en) 2015-03-06 2018-03-27 Ethicon Endo-Surgery, Llc Interactive feedback system for powered surgical instruments
US10045776B2 (en) 2015-03-06 2018-08-14 Ethicon Llc Control techniques and sub-processor contained within modular shaft with select control processing from handle
US9895148B2 (en) 2015-03-06 2018-02-20 Ethicon Endo-Surgery, Llc Monitoring speed control and precision incrementing of motor for powered surgical instruments
US10548504B2 (en) 2015-03-06 2020-02-04 Ethicon Llc Overlaid multi sensor radio frequency (RF) electrode system to measure tissue compression
US10687806B2 (en) 2015-03-06 2020-06-23 Ethicon Llc Adaptive tissue compression techniques to adjust closure rates for multiple tissue types
US9993248B2 (en) 2015-03-06 2018-06-12 Ethicon Endo-Surgery, Llc Smart sensors with local signal processing
US9901342B2 (en) 2015-03-06 2018-02-27 Ethicon Endo-Surgery, Llc Signal and power communication system positioned on a rotatable shaft
US9808246B2 (en) 2015-03-06 2017-11-07 Ethicon Endo-Surgery, Llc Method of operating a powered surgical instrument
US10213201B2 (en) 2015-03-31 2019-02-26 Ethicon Llc Stapling end effector configured to compensate for an uneven gap between a first jaw and a second jaw
US10449055B2 (en) 2015-04-23 2019-10-22 Disc Fix L.L.C. Systems and methods for treatment of intervertebral disc derangements
US9867974B2 (en) * 2015-06-01 2018-01-16 Wisconsin Alumni Research Foundation Microfluidic device for multiplexed point source administration of compounds
US10499832B2 (en) 2015-06-05 2019-12-10 Cianna Medical, Inc. Reflector markers and systems and methods for identifying and locating them
US10610326B2 (en) 2015-06-05 2020-04-07 Cianna Medical, Inc. Passive tags, and systems and methods for using them
US10368861B2 (en) 2015-06-18 2019-08-06 Ethicon Llc Dual articulation drive system arrangements for articulatable surgical instruments
US11058425B2 (en) 2015-08-17 2021-07-13 Ethicon Llc Implantable layers for a surgical instrument
US10596330B2 (en) 2015-08-26 2020-03-24 Medtronic Xomed, Inc. Resorbable, drug-eluting submucosal turbinate implant device and method
US10357251B2 (en) 2015-08-26 2019-07-23 Ethicon Llc Surgical staples comprising hardness variations for improved fastening of tissue
JP6828018B2 (en) 2015-08-26 2021-02-10 エシコン エルエルシーＥｔｈｉｃｏｎ ＬＬＣ Surgical staple strips that allow you to change the characteristics of staples and facilitate filling into cartridges
US10569071B2 (en) 2015-08-31 2020-02-25 Ethicon Llc Medicant eluting adjuncts and methods of using medicant eluting adjuncts
US10111661B2 (en) * 2015-08-31 2018-10-30 Ethicon Llc Matrix metalloproteinase inhibiting adjuncts for surgical devices
US10238390B2 (en) 2015-09-02 2019-03-26 Ethicon Llc Surgical staple cartridges with driver arrangements for establishing herringbone staple patterns
MX2022006192A (en) 2015-09-02 2022-06-16 Ethicon Llc Surgical staple configurations with camming surfaces located between portions supporting surgical staples.
US10327769B2 (en) 2015-09-23 2019-06-25 Ethicon Llc Surgical stapler having motor control based on a drive system component
US10076326B2 (en) 2015-09-23 2018-09-18 Ethicon Llc Surgical stapler having current mirror-based motor control
US10238386B2 (en) 2015-09-23 2019-03-26 Ethicon Llc Surgical stapler having motor control based on an electrical parameter related to a motor current
US10105139B2 (en) 2015-09-23 2018-10-23 Ethicon Llc Surgical stapler having downstream current-based motor control
US10363036B2 (en) 2015-09-23 2019-07-30 Ethicon Llc Surgical stapler having force-based motor control
US10085751B2 (en) 2015-09-23 2018-10-02 Ethicon Llc Surgical stapler having temperature-based motor control
US10299878B2 (en) 2015-09-25 2019-05-28 Ethicon Llc Implantable adjunct systems for determining adjunct skew
US10285699B2 (en) 2015-09-30 2019-05-14 Ethicon Llc Compressible adjunct
US11890015B2 (en) 2015-09-30 2024-02-06 Cilag Gmbh International Compressible adjunct with crossing spacer fibers
US10327777B2 (en) 2015-09-30 2019-06-25 Ethicon Llc Implantable layer comprising plastically deformed fibers
US10980539B2 (en) 2015-09-30 2021-04-20 Ethicon Llc Implantable adjunct comprising bonded layers
US10292704B2 (en) 2015-12-30 2019-05-21 Ethicon Llc Mechanisms for compensating for battery pack failure in powered surgical instruments
US10265068B2 (en) 2015-12-30 2019-04-23 Ethicon Llc Surgical instruments with separable motors and motor control circuits
US10368865B2 (en) 2015-12-30 2019-08-06 Ethicon Llc Mechanisms for compensating for drivetrain failure in powered surgical instruments
US20170224332A1 (en) 2016-02-09 2017-08-10 Ethicon Endo-Surgery, Llc Surgical instruments with non-symmetrical articulation arrangements
BR112018016098B1 (en) 2016-02-09 2023-02-23 Ethicon Llc SURGICAL INSTRUMENT
US11213293B2 (en) 2016-02-09 2022-01-04 Cilag Gmbh International Articulatable surgical instruments with single articulation link arrangements
US10258331B2 (en) 2016-02-12 2019-04-16 Ethicon Llc Mechanisms for compensating for drivetrain failure in powered surgical instruments
US11224426B2 (en) 2016-02-12 2022-01-18 Cilag Gmbh International Mechanisms for compensating for drivetrain failure in powered surgical instruments
US10448948B2 (en) 2016-02-12 2019-10-22 Ethicon Llc Mechanisms for compensating for drivetrain failure in powered surgical instruments
AU2017226261A1 (en) 2016-03-03 2018-10-04 Cianna Medical, Inc. Implantable markers, and systems and methods for using them
US10226550B2 (en) 2016-03-11 2019-03-12 Brigham Young University Cationic steroidal antimicrobial compositions for the treatment of dermal tissue
US11064997B2 (en) 2016-04-01 2021-07-20 Cilag Gmbh International Surgical stapling instrument
US10617413B2 (en) 2016-04-01 2020-04-14 Ethicon Llc Closure system arrangements for surgical cutting and stapling devices with separate and distinct firing shafts
US10827949B2 (en) 2016-04-06 2020-11-10 Cianna Medical, Inc. Reflector markers and systems and methods for identifying and locating them
US10828028B2 (en) 2016-04-15 2020-11-10 Ethicon Llc Surgical instrument with multiple program responses during a firing motion
US10357247B2 (en) 2016-04-15 2019-07-23 Ethicon Llc Surgical instrument with multiple program responses during a firing motion
US10492783B2 (en) 2016-04-15 2019-12-03 Ethicon, Llc Surgical instrument with improved stop/start control during a firing motion
US10456137B2 (en) 2016-04-15 2019-10-29 Ethicon Llc Staple formation detection mechanisms
US11607239B2 (en) 2016-04-15 2023-03-21 Cilag Gmbh International Systems and methods for controlling a surgical stapling and cutting instrument
US10426467B2 (en) 2016-04-15 2019-10-01 Ethicon Llc Surgical instrument with detection sensors
US10405859B2 (en) 2016-04-15 2019-09-10 Ethicon Llc Surgical instrument with adjustable stop/start control during a firing motion
US11179150B2 (en) 2016-04-15 2021-11-23 Cilag Gmbh International Systems and methods for controlling a surgical stapling and cutting instrument
US10335145B2 (en) 2016-04-15 2019-07-02 Ethicon Llc Modular surgical instrument with configurable operating mode
US20170296173A1 (en) 2016-04-18 2017-10-19 Ethicon Endo-Surgery, Llc Method for operating a surgical instrument
US10368867B2 (en) 2016-04-18 2019-08-06 Ethicon Llc Surgical instrument comprising a lockout
US11317917B2 (en) 2016-04-18 2022-05-03 Cilag Gmbh International Surgical stapling system comprising a lockable firing assembly
CN105943531B (en) * 2016-05-05 2018-09-28 香港中文大学深圳研究院 Bis- (adjacent aminobenzene sulfydryl) applications of the butadiene in pharmacy of 1,4- diamino -2,3- dicyanos -1,4-
JP6957532B2 (en) 2016-06-24 2021-11-02 エシコン エルエルシーＥｔｈｉｃｏｎ ＬＬＣ Staple cartridges including wire staples and punched staples
USD850617S1 (en) 2016-06-24 2019-06-04 Ethicon Llc Surgical fastener cartridge
USD826405S1 (en) 2016-06-24 2018-08-21 Ethicon Llc Surgical fastener
US10702270B2 (en) 2016-06-24 2020-07-07 Ethicon Llc Stapling system for use with wire staples and stamped staples
USD847989S1 (en) 2016-06-24 2019-05-07 Ethicon Llc Surgical fastener cartridge
US10188602B2 (en) 2016-09-29 2019-01-29 Gesea Biosciences Inc. Bioerodible implant for long-term drug delivery and associated methods of manufacture and use
JP7010956B2 (en) 2016-12-21 2022-01-26 エシコン エルエルシー How to staple tissue
US20180168648A1 (en) 2016-12-21 2018-06-21 Ethicon Endo-Surgery, Llc Durability features for end effectors and firing assemblies of surgical stapling instruments
US10568624B2 (en) 2016-12-21 2020-02-25 Ethicon Llc Surgical instruments with jaws that are pivotable about a fixed axis and include separate and distinct closure and firing systems
US20180168615A1 (en) 2016-12-21 2018-06-21 Ethicon Endo-Surgery, Llc Method of deforming staples from two different types of staple cartridges with the same surgical stapling instrument
US10918385B2 (en) 2016-12-21 2021-02-16 Ethicon Llc Surgical system comprising a firing member rotatable into an articulation state to articulate an end effector of the surgical system
US11419606B2 (en) 2016-12-21 2022-08-23 Cilag Gmbh International Shaft assembly comprising a clutch configured to adapt the output of a rotary firing member to two different systems
US10945727B2 (en) 2016-12-21 2021-03-16 Ethicon Llc Staple cartridge with deformable driver retention features
CN110099619B (en) 2016-12-21 2022-07-15 爱惜康有限责任公司 Lockout device for surgical end effector and replaceable tool assembly
US10888322B2 (en) 2016-12-21 2021-01-12 Ethicon Llc Surgical instrument comprising a cutting member
US10856868B2 (en) 2016-12-21 2020-12-08 Ethicon Llc Firing member pin configurations
US10959727B2 (en) 2016-12-21 2021-03-30 Ethicon Llc Articulatable surgical end effector with asymmetric shaft arrangement
US10682138B2 (en) 2016-12-21 2020-06-16 Ethicon Llc Bilaterally asymmetric staple forming pocket pairs
US10426471B2 (en) 2016-12-21 2019-10-01 Ethicon Llc Surgical instrument with multiple failure response modes
US10588631B2 (en) 2016-12-21 2020-03-17 Ethicon Llc Surgical instruments with positive jaw opening features
US10695055B2 (en) 2016-12-21 2020-06-30 Ethicon Llc Firing assembly comprising a lockout
US20180168633A1 (en) 2016-12-21 2018-06-21 Ethicon Endo-Surgery, Llc Surgical stapling instruments and staple-forming anvils
US10973516B2 (en) 2016-12-21 2021-04-13 Ethicon Llc Surgical end effectors and adaptable firing members therefor
US11684367B2 (en) 2016-12-21 2023-06-27 Cilag Gmbh International Stepped assembly having and end-of-life indicator
US20180168625A1 (en) 2016-12-21 2018-06-21 Ethicon Endo-Surgery, Llc Surgical stapling instruments with smart staple cartridges
US10993715B2 (en) 2016-12-21 2021-05-04 Ethicon Llc Staple cartridge comprising staples with different clamping breadths
MX2019007311A (en) 2016-12-21 2019-11-18 Ethicon Llc Surgical stapling systems.
US10687810B2 (en) 2016-12-21 2020-06-23 Ethicon Llc Stepped staple cartridge with tissue retention and gap setting features
US11134942B2 (en) 2016-12-21 2021-10-05 Cilag Gmbh International Surgical stapling instruments and staple-forming anvils
US11090048B2 (en) 2016-12-21 2021-08-17 Cilag Gmbh International Method for resetting a fuse of a surgical instrument shaft
CN106730418A (en) * 2017-02-06 2017-05-31 浙江荣诚医疗科技有限公司 A kind of titanium mark implant
US10959433B2 (en) 2017-03-21 2021-03-30 Brigham Young University Use of cationic steroidal antimicrobials for sporicidal activity
US10307170B2 (en) 2017-06-20 2019-06-04 Ethicon Llc Method for closed loop control of motor velocity of a surgical stapling and cutting instrument
US10646220B2 (en) 2017-06-20 2020-05-12 Ethicon Llc Systems and methods for controlling displacement member velocity for a surgical instrument
US10368864B2 (en) 2017-06-20 2019-08-06 Ethicon Llc Systems and methods for controlling displaying motor velocity for a surgical instrument
US10980537B2 (en) 2017-06-20 2021-04-20 Ethicon Llc Closed loop feedback control of motor velocity of a surgical stapling and cutting instrument based on measured time over a specified number of shaft rotations
US10888321B2 (en) 2017-06-20 2021-01-12 Ethicon Llc Systems and methods for controlling velocity of a displacement member of a surgical stapling and cutting instrument
US10813639B2 (en) 2017-06-20 2020-10-27 Ethicon Llc Closed loop feedback control of motor velocity of a surgical stapling and cutting instrument based on system conditions
US11517325B2 (en) 2017-06-20 2022-12-06 Cilag Gmbh International Closed loop feedback control of motor velocity of a surgical stapling and cutting instrument based on measured displacement distance traveled over a specified time interval
US10881399B2 (en) 2017-06-20 2021-01-05 Ethicon Llc Techniques for adaptive control of motor velocity of a surgical stapling and cutting instrument
US11382638B2 (en) 2017-06-20 2022-07-12 Cilag Gmbh International Closed loop feedback control of motor velocity of a surgical stapling and cutting instrument based on measured time over a specified displacement distance
US10327767B2 (en) 2017-06-20 2019-06-25 Ethicon Llc Control of motor velocity of a surgical stapling and cutting instrument based on angle of articulation
US10624633B2 (en) 2017-06-20 2020-04-21 Ethicon Llc Systems and methods for controlling motor velocity of a surgical stapling and cutting instrument
US10779820B2 (en) 2017-06-20 2020-09-22 Ethicon Llc Systems and methods for controlling motor speed according to user input for a surgical instrument
USD879809S1 (en) 2017-06-20 2020-03-31 Ethicon Llc Display panel with changeable graphical user interface
USD879808S1 (en) 2017-06-20 2020-03-31 Ethicon Llc Display panel with graphical user interface
US11090046B2 (en) 2017-06-20 2021-08-17 Cilag Gmbh International Systems and methods for controlling displacement member motion of a surgical stapling and cutting instrument
US10881396B2 (en) 2017-06-20 2021-01-05 Ethicon Llc Surgical instrument with variable duration trigger arrangement
USD890784S1 (en) 2017-06-20 2020-07-21 Ethicon Llc Display panel with changeable graphical user interface
US10390841B2 (en) 2017-06-20 2019-08-27 Ethicon Llc Control of motor velocity of a surgical stapling and cutting instrument based on angle of articulation
US11653914B2 (en) 2017-06-20 2023-05-23 Cilag Gmbh International Systems and methods for controlling motor velocity of a surgical stapling and cutting instrument according to articulation angle of end effector
US11071554B2 (en) 2017-06-20 2021-07-27 Cilag Gmbh International Closed loop feedback control of motor velocity of a surgical stapling and cutting instrument based on magnitude of velocity error measurements
US10856869B2 (en) 2017-06-27 2020-12-08 Ethicon Llc Surgical anvil arrangements
US10993716B2 (en) 2017-06-27 2021-05-04 Ethicon Llc Surgical anvil arrangements
US10772629B2 (en) 2017-06-27 2020-09-15 Ethicon Llc Surgical anvil arrangements
US20180368844A1 (en) 2017-06-27 2018-12-27 Ethicon Llc Staple forming pocket arrangements
US11324503B2 (en) 2017-06-27 2022-05-10 Cilag Gmbh International Surgical firing member arrangements
US11266405B2 (en) 2017-06-27 2022-03-08 Cilag Gmbh International Surgical anvil manufacturing methods
US11484310B2 (en) 2017-06-28 2022-11-01 Cilag Gmbh International Surgical instrument comprising a shaft including a closure tube profile
EP3420947B1 (en) 2017-06-28 2022-05-25 Cilag GmbH International Surgical instrument comprising selectively actuatable rotatable couplers
US11564686B2 (en) 2017-06-28 2023-01-31 Cilag Gmbh International Surgical shaft assemblies with flexible interfaces
USD854151S1 (en) 2017-06-28 2019-07-16 Ethicon Llc Surgical instrument shaft
US10903685B2 (en) 2017-06-28 2021-01-26 Ethicon Llc Surgical shaft assemblies with slip ring assemblies forming capacitive channels
USD851762S1 (en) 2017-06-28 2019-06-18 Ethicon Llc Anvil
US10211586B2 (en) 2017-06-28 2019-02-19 Ethicon Llc Surgical shaft assemblies with watertight housings
USD906355S1 (en) 2017-06-28 2020-12-29 Ethicon Llc Display screen or portion thereof with a graphical user interface for a surgical instrument
USD869655S1 (en) 2017-06-28 2019-12-10 Ethicon Llc Surgical fastener cartridge
US11246592B2 (en) 2017-06-28 2022-02-15 Cilag Gmbh International Surgical instrument comprising an articulation system lockable to a frame
US11478242B2 (en) 2017-06-28 2022-10-25 Cilag Gmbh International Jaw retainer arrangement for retaining a pivotable surgical instrument jaw in pivotable retaining engagement with a second surgical instrument jaw
US10716614B2 (en) 2017-06-28 2020-07-21 Ethicon Llc Surgical shaft assemblies with slip ring assemblies with increased contact pressure
US11259805B2 (en) 2017-06-28 2022-03-01 Cilag Gmbh International Surgical instrument comprising firing member supports
US10765427B2 (en) 2017-06-28 2020-09-08 Ethicon Llc Method for articulating a surgical instrument
US10898183B2 (en) 2017-06-29 2021-01-26 Ethicon Llc Robotic surgical instrument with closed loop feedback techniques for advancement of closure member during firing
US10932772B2 (en) 2017-06-29 2021-03-02 Ethicon Llc Methods for closed loop velocity control for robotic surgical instrument
US11007022B2 (en) 2017-06-29 2021-05-18 Ethicon Llc Closed loop velocity control techniques based on sensed tissue parameters for robotic surgical instrument
US10398434B2 (en) 2017-06-29 2019-09-03 Ethicon Llc Closed loop velocity control of closure member for robotic surgical instrument
US10258418B2 (en) 2017-06-29 2019-04-16 Ethicon Llc System for controlling articulation forces
US11471155B2 (en) 2017-08-03 2022-10-18 Cilag Gmbh International Surgical system bailout
US11304695B2 (en) 2017-08-03 2022-04-19 Cilag Gmbh International Surgical system shaft interconnection
US11944300B2 (en) 2017-08-03 2024-04-02 Cilag Gmbh International Method for operating a surgical system bailout
CN111712228A (en) 2017-09-15 2020-09-25 奥叙拉尔有限公司 Ophthalmic pharmaceutical composition
US10729501B2 (en) 2017-09-29 2020-08-04 Ethicon Llc Systems and methods for language selection of a surgical instrument
US10796471B2 (en) 2017-09-29 2020-10-06 Ethicon Llc Systems and methods of displaying a knife position for a surgical instrument
US10743872B2 (en) 2017-09-29 2020-08-18 Ethicon Llc System and methods for controlling a display of a surgical instrument
USD907648S1 (en) 2017-09-29 2021-01-12 Ethicon Llc Display screen or portion thereof with animated graphical user interface
USD917500S1 (en) 2017-09-29 2021-04-27 Ethicon Llc Display screen or portion thereof with graphical user interface
USD907647S1 (en) 2017-09-29 2021-01-12 Ethicon Llc Display screen or portion thereof with animated graphical user interface
US11399829B2 (en) 2017-09-29 2022-08-02 Cilag Gmbh International Systems and methods of initiating a power shutdown mode for a surgical instrument
US10765429B2 (en) 2017-09-29 2020-09-08 Ethicon Llc Systems and methods for providing alerts according to the operational state of a surgical instrument
WO2019071245A1 (en) 2017-10-06 2019-04-11 Foundry Therapeutics, Inc. Implantable depots for controlled release of analgesics to treat postoperative pain associated with orthopedic surgery, and associated devices, systems, and methods
US11134944B2 (en) 2017-10-30 2021-10-05 Cilag Gmbh International Surgical stapler knife motion controls
US11090075B2 (en) 2017-10-30 2021-08-17 Cilag Gmbh International Articulation features for surgical end effector
US10779903B2 (en) 2017-10-31 2020-09-22 Ethicon Llc Positive shaft rotation lock activated by jaw closure
US10842490B2 (en) 2017-10-31 2020-11-24 Ethicon Llc Cartridge body design with force reduction based on firing completion
KR102089737B1 (en) * 2017-11-01 2020-03-16 한국화학연구원 A sustained-release injection of microspheres containing escitalopram and manufacturing method thereof
US10869666B2 (en) 2017-12-15 2020-12-22 Ethicon Llc Adapters with control systems for controlling multiple motors of an electromechanical surgical instrument
US11071543B2 (en) 2017-12-15 2021-07-27 Cilag Gmbh International Surgical end effectors with clamping assemblies configured to increase jaw aperture ranges
US10687813B2 (en) 2017-12-15 2020-06-23 Ethicon Llc Adapters with firing stroke sensing arrangements for use in connection with electromechanical surgical instruments
US10779826B2 (en) 2017-12-15 2020-09-22 Ethicon Llc Methods of operating surgical end effectors
US10966718B2 (en) 2017-12-15 2021-04-06 Ethicon Llc Dynamic clamping assemblies with improved wear characteristics for use in connection with electromechanical surgical instruments
US10743874B2 (en) 2017-12-15 2020-08-18 Ethicon Llc Sealed adapters for use with electromechanical surgical instruments
US11033267B2 (en) 2017-12-15 2021-06-15 Ethicon Llc Systems and methods of controlling a clamping member firing rate of a surgical instrument
US10828033B2 (en) 2017-12-15 2020-11-10 Ethicon Llc Handheld electromechanical surgical instruments with improved motor control arrangements for positioning components of an adapter coupled thereto
US10743875B2 (en) 2017-12-15 2020-08-18 Ethicon Llc Surgical end effectors with jaw stiffener arrangements configured to permit monitoring of firing member
US11197670B2 (en) 2017-12-15 2021-12-14 Cilag Gmbh International Surgical end effectors with pivotal jaws configured to touch at their respective distal ends when fully closed
US11006955B2 (en) 2017-12-15 2021-05-18 Ethicon Llc End effectors with positive jaw opening features for use with adapters for electromechanical surgical instruments
US10779825B2 (en) 2017-12-15 2020-09-22 Ethicon Llc Adapters with end effector position sensing and control arrangements for use in connection with electromechanical surgical instruments
US10729509B2 (en) 2017-12-19 2020-08-04 Ethicon Llc Surgical instrument comprising closure and firing locking mechanism
US10716565B2 (en) 2017-12-19 2020-07-21 Ethicon Llc Surgical instruments with dual articulation drivers
US10835330B2 (en) 2017-12-19 2020-11-17 Ethicon Llc Method for determining the position of a rotatable jaw of a surgical instrument attachment assembly
USD910847S1 (en) 2017-12-19 2021-02-16 Ethicon Llc Surgical instrument assembly
US11020112B2 (en) 2017-12-19 2021-06-01 Ethicon Llc Surgical tools configured for interchangeable use with different controller interfaces
US11045270B2 (en) 2017-12-19 2021-06-29 Cilag Gmbh International Robotic attachment comprising exterior drive actuator
US11076853B2 (en) 2017-12-21 2021-08-03 Cilag Gmbh International Systems and methods of displaying a knife position during transection for a surgical instrument
US11129680B2 (en) 2017-12-21 2021-09-28 Cilag Gmbh International Surgical instrument comprising a projector
US11179152B2 (en) 2017-12-21 2021-11-23 Cilag Gmbh International Surgical instrument comprising a tissue grasping system
US11311290B2 (en) 2017-12-21 2022-04-26 Cilag Gmbh International Surgical instrument comprising an end effector dampener
CN210354877U (en) * 2018-02-12 2020-04-21 香港科能有限公司 Drug-releasing implant
US11116876B2 (en) * 2018-02-20 2021-09-14 Shu-Tung And Alice Li Foundation Inc. Methods and devices for repair of severed peripheral nerves with erythropoietin
KR102114474B1 (en) * 2018-06-26 2020-05-22 랩앤피플주식회사 Hypodermatic capsule made of bioabsorbable material for vaccination
US11207065B2 (en) 2018-08-20 2021-12-28 Cilag Gmbh International Method for fabricating surgical stapler anvils
US11291440B2 (en) 2018-08-20 2022-04-05 Cilag Gmbh International Method for operating a powered articulatable surgical instrument
US11324501B2 (en) 2018-08-20 2022-05-10 Cilag Gmbh International Surgical stapling devices with improved closure members
US11045192B2 (en) 2018-08-20 2021-06-29 Cilag Gmbh International Fabricating techniques for surgical stapler anvils
US11083458B2 (en) 2018-08-20 2021-08-10 Cilag Gmbh International Powered surgical instruments with clutching arrangements to convert linear drive motions to rotary drive motions
USD914878S1 (en) 2018-08-20 2021-03-30 Ethicon Llc Surgical instrument anvil
US11039834B2 (en) 2018-08-20 2021-06-22 Cilag Gmbh International Surgical stapler anvils with staple directing protrusions and tissue stability features
US10779821B2 (en) 2018-08-20 2020-09-22 Ethicon Llc Surgical stapler anvils with tissue stop features configured to avoid tissue pinch
US11253256B2 (en) 2018-08-20 2022-02-22 Cilag Gmbh International Articulatable motor powered surgical instruments with dedicated articulation motor arrangements
US10912559B2 (en) 2018-08-20 2021-02-09 Ethicon Llc Reinforced deformable anvil tip for surgical stapler anvil
US10856870B2 (en) 2018-08-20 2020-12-08 Ethicon Llc Switching arrangements for motor powered articulatable surgical instruments
US10842492B2 (en) 2018-08-20 2020-11-24 Ethicon Llc Powered articulatable surgical instruments with clutching and locking arrangements for linking an articulation drive system to a firing drive system
WO2020047766A1 (en) * 2018-09-05 2020-03-12 Jmd Innovation Inc. Position marker and delivery system
US11883150B2 (en) 2018-09-06 2024-01-30 Cianna Medical, Inc. Systems for identifying and locating reflectors using orthogonal sequences of reflector switching
SG11202103220VA (en) 2018-10-30 2021-05-28 Hoffmann La Roche Implantation needle and kit
DE102018127200B3 (en) * 2018-10-31 2019-07-25 Andreas Haas IMPLANT TO SUBCUTANEOUS IMPLANT
US11147553B2 (en) 2019-03-25 2021-10-19 Cilag Gmbh International Firing drive arrangements for surgical systems
US11696761B2 (en) 2019-03-25 2023-07-11 Cilag Gmbh International Firing drive arrangements for surgical systems
US11147551B2 (en) 2019-03-25 2021-10-19 Cilag Gmbh International Firing drive arrangements for surgical systems
US11172929B2 (en) 2019-03-25 2021-11-16 Cilag Gmbh International Articulation drive arrangements for surgical systems
US11690974B2 (en) 2019-04-25 2023-07-04 Warsaw Orthopedic, Inc. Methods and devices for delivering therapeutic materials to the intervertebral disc
US11648009B2 (en) 2019-04-30 2023-05-16 Cilag Gmbh International Rotatable jaw tip for a surgical instrument
US11903581B2 (en) 2019-04-30 2024-02-20 Cilag Gmbh International Methods for stapling tissue using a surgical instrument
US11471157B2 (en) 2019-04-30 2022-10-18 Cilag Gmbh International Articulation control mapping for a surgical instrument
US11432816B2 (en) 2019-04-30 2022-09-06 Cilag Gmbh International Articulation pin for a surgical instrument
US11253254B2 (en) 2019-04-30 2022-02-22 Cilag Gmbh International Shaft rotation actuator on a surgical instrument
US11452528B2 (en) 2019-04-30 2022-09-27 Cilag Gmbh International Articulation actuators for a surgical instrument
US11426251B2 (en) 2019-04-30 2022-08-30 Cilag Gmbh International Articulation directional lights on a surgical instrument
US11553971B2 (en) 2019-06-28 2023-01-17 Cilag Gmbh International Surgical RFID assemblies for display and communication
US11660163B2 (en) 2019-06-28 2023-05-30 Cilag Gmbh International Surgical system with RFID tags for updating motor assembly parameters
US11224497B2 (en) 2019-06-28 2022-01-18 Cilag Gmbh International Surgical systems with multiple RFID tags
US11051807B2 (en) 2019-06-28 2021-07-06 Cilag Gmbh International Packaging assembly including a particulate trap
US11478241B2 (en) 2019-06-28 2022-10-25 Cilag Gmbh International Staple cartridge including projections
US11426167B2 (en) 2019-06-28 2022-08-30 Cilag Gmbh International Mechanisms for proper anvil attachment surgical stapling head assembly
US11350938B2 (en) 2019-06-28 2022-06-07 Cilag Gmbh International Surgical instrument comprising an aligned rfid sensor
US11464601B2 (en) 2019-06-28 2022-10-11 Cilag Gmbh International Surgical instrument comprising an RFID system for tracking a movable component
US11246678B2 (en) 2019-06-28 2022-02-15 Cilag Gmbh International Surgical stapling system having a frangible RFID tag
US11298127B2 (en) 2019-06-28 2022-04-12 Cilag GmbH Interational Surgical stapling system having a lockout mechanism for an incompatible cartridge
US11399837B2 (en) 2019-06-28 2022-08-02 Cilag Gmbh International Mechanisms for motor control adjustments of a motorized surgical instrument
US11259803B2 (en) 2019-06-28 2022-03-01 Cilag Gmbh International Surgical stapling system having an information encryption protocol
US11298132B2 (en) 2019-06-28 2022-04-12 Cilag GmbH Inlernational Staple cartridge including a honeycomb extension
US11219455B2 (en) 2019-06-28 2022-01-11 Cilag Gmbh International Surgical instrument including a lockout key
US11684434B2 (en) 2019-06-28 2023-06-27 Cilag Gmbh International Surgical RFID assemblies for instrument operational setting control
US11376098B2 (en) 2019-06-28 2022-07-05 Cilag Gmbh International Surgical instrument system comprising an RFID system
US11523822B2 (en) 2019-06-28 2022-12-13 Cilag Gmbh International Battery pack including a circuit interrupter
US11771419B2 (en) 2019-06-28 2023-10-03 Cilag Gmbh International Packaging for a replaceable component of a surgical stapling system
US11638587B2 (en) 2019-06-28 2023-05-02 Cilag Gmbh International RFID identification systems for surgical instruments
US11291451B2 (en) 2019-06-28 2022-04-05 Cilag Gmbh International Surgical instrument with battery compatibility verification functionality
US11497492B2 (en) 2019-06-28 2022-11-15 Cilag Gmbh International Surgical instrument including an articulation lock
US11627959B2 (en) 2019-06-28 2023-04-18 Cilag Gmbh International Surgical instruments including manual and powered system lockouts
US11446029B2 (en) 2019-12-19 2022-09-20 Cilag Gmbh International Staple cartridge comprising projections extending from a curved deck surface
US11304696B2 (en) 2019-12-19 2022-04-19 Cilag Gmbh International Surgical instrument comprising a powered articulation system
US11529139B2 (en) 2019-12-19 2022-12-20 Cilag Gmbh International Motor driven surgical instrument
US11234698B2 (en) 2019-12-19 2022-02-01 Cilag Gmbh International Stapling system comprising a clamp lockout and a firing lockout
US11911032B2 (en) 2019-12-19 2024-02-27 Cilag Gmbh International Staple cartridge comprising a seating cam
US11504122B2 (en) 2019-12-19 2022-11-22 Cilag Gmbh International Surgical instrument comprising a nested firing member
US11529137B2 (en) 2019-12-19 2022-12-20 Cilag Gmbh International Staple cartridge comprising driver retention members
US11576672B2 (en) 2019-12-19 2023-02-14 Cilag Gmbh International Surgical instrument comprising a closure system including a closure member and an opening member driven by a drive screw
US11464512B2 (en) 2019-12-19 2022-10-11 Cilag Gmbh International Staple cartridge comprising a curved deck surface
US11701111B2 (en) 2019-12-19 2023-07-18 Cilag Gmbh International Method for operating a surgical stapling instrument
US11844520B2 (en) 2019-12-19 2023-12-19 Cilag Gmbh International Staple cartridge comprising driver retention members
US11291447B2 (en) 2019-12-19 2022-04-05 Cilag Gmbh International Stapling instrument comprising independent jaw closing and staple firing systems
US11559304B2 (en) 2019-12-19 2023-01-24 Cilag Gmbh International Surgical instrument comprising a rapid closure mechanism
US11607219B2 (en) 2019-12-19 2023-03-21 Cilag Gmbh International Staple cartridge comprising a detachable tissue cutting knife
US11931033B2 (en) 2019-12-19 2024-03-19 Cilag Gmbh International Staple cartridge comprising a latch lockout
US20230158281A1 (en) * 2020-04-10 2023-05-25 The Regents Of The University Of California Systems, devices, and methods for delivering a substance within a target tissue
USD967421S1 (en) 2020-06-02 2022-10-18 Cilag Gmbh International Staple cartridge
USD975278S1 (en) 2020-06-02 2023-01-10 Cilag Gmbh International Staple cartridge
USD976401S1 (en) 2020-06-02 2023-01-24 Cilag Gmbh International Staple cartridge
USD975850S1 (en) 2020-06-02 2023-01-17 Cilag Gmbh International Staple cartridge
USD966512S1 (en) 2020-06-02 2022-10-11 Cilag Gmbh International Staple cartridge
USD974560S1 (en) 2020-06-02 2023-01-03 Cilag Gmbh International Staple cartridge
USD975851S1 (en) 2020-06-02 2023-01-17 Cilag Gmbh International Staple cartridge
US20220031320A1 (en) 2020-07-28 2022-02-03 Cilag Gmbh International Surgical instruments with flexible firing member actuator constraint arrangements
USD1013170S1 (en) 2020-10-29 2024-01-30 Cilag Gmbh International Surgical instrument assembly
USD980425S1 (en) 2020-10-29 2023-03-07 Cilag Gmbh International Surgical instrument assembly
US11717289B2 (en) 2020-10-29 2023-08-08 Cilag Gmbh International Surgical instrument comprising an indicator which indicates that an articulation drive is actuatable
US11617577B2 (en) 2020-10-29 2023-04-04 Cilag Gmbh International Surgical instrument comprising a sensor configured to sense whether an articulation drive of the surgical instrument is actuatable
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US11857183B2 (en) 2021-03-24 2024-01-02 Cilag Gmbh International Stapling assembly components having metal substrates and plastic bodies
US11826047B2 (en) 2021-05-28 2023-11-28 Cilag Gmbh International Stapling instrument comprising jaw mounts
US11877745B2 (en) 2021-10-18 2024-01-23 Cilag Gmbh International Surgical stapling assembly having longitudinally-repeating staple leg clusters
US11937816B2 (en) 2021-10-28 2024-03-26 Cilag Gmbh International Electrical lead arrangements for surgical instruments
CN114432587B (en) * 2021-12-14 2022-09-20 优微（珠海）生物科技有限公司 Microneedle patch

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5489308A (en) * 1989-07-06 1996-02-06 Spine-Tech, Inc. Spinal implant
US20040230303A1 (en) * 2003-05-16 2004-11-18 Gomes Katherine A. Cartilage allograft plug
EP1491233A1 (en) * 2002-03-26 2004-12-29 Juridical Foundation Osaka Industrial Promotion Organization Medical treatment system and production method therefor
WO2005070333A1 (en) * 2004-01-13 2005-08-04 Orthobiologica, Inc. Drug delivery to a joint

Family Cites Families (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5733572A (en) * 1989-12-22 1998-03-31 Imarx Pharmaceutical Corp. Gas and gaseous precursor filled microspheres as topical and subcutaneous delivery vehicles
US7083572B2 (en) * 1993-11-30 2006-08-01 Bristol-Myers Squibb Medical Imaging, Inc. Therapeutic delivery systems
US8795242B2 (en) 1994-05-13 2014-08-05 Kensey Nash Corporation Resorbable polymeric device for localized drug delivery
US7963997B2 (en) 2002-07-19 2011-06-21 Kensey Nash Corporation Device for regeneration of articular cartilage and other tissue
US5756127A (en) * 1996-10-29 1998-05-26 Wright Medical Technology, Inc. Implantable bioresorbable string of calcium sulfate beads
US6203813B1 (en) 1997-01-13 2001-03-20 Lance L. Gooberman Pharmaceutical delivery device and method of preparation therefor
AU6517900A (en) * 1999-08-03 2001-02-19 Smith & Nephew, Inc. Controlled release implantable devices
US6478776B1 (en) 2000-04-05 2002-11-12 Biocardia, Inc. Implant delivery catheter system and methods for its use
US6673333B1 (en) * 2000-05-04 2004-01-06 Research Corporation Technologies, Inc. Functional MRI agents for cancer imaging
US6530934B1 (en) * 2000-06-06 2003-03-11 Sarcos Lc Embolic device composed of a linear sequence of miniature beads
US6735475B1 (en) 2001-01-30 2004-05-11 Advanced Bionics Corporation Fully implantable miniature neurostimulator for stimulation as a therapy for headache and/or facial pain
US7166133B2 (en) 2002-06-13 2007-01-23 Kensey Nash Corporation Devices and methods for treating defects in the tissue of a living being
US20040229878A1 (en) * 2003-05-13 2004-11-18 Depuy Spine, Inc. Transdiscal administration of specific inhibitors of P38 kinase
US8361467B2 (en) * 2003-07-30 2013-01-29 Depuy Spine, Inc. Trans-capsular administration of high specificity cytokine inhibitors into orthopedic joints
US8747881B2 (en) 2003-12-19 2014-06-10 Cordis Corporation Intraluminal medical devices in combination with therapeutic agents
US7361168B2 (en) 2004-04-21 2008-04-22 Acclarent, Inc. Implantable device and methods for delivering drugs and other substances to treat sinusitis and other disorders
US20060046961A1 (en) 2004-09-02 2006-03-02 Mckay William F Controlled and directed local delivery of anti-inflammatory compositions
US7741273B2 (en) * 2006-04-13 2010-06-22 Warsaw Orthopedic, Inc. Drug depot implant designs

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5489308A (en) * 1989-07-06 1996-02-06 Spine-Tech, Inc. Spinal implant
EP1491233A1 (en) * 2002-03-26 2004-12-29 Juridical Foundation Osaka Industrial Promotion Organization Medical treatment system and production method therefor
US20040230303A1 (en) * 2003-05-16 2004-11-18 Gomes Katherine A. Cartilage allograft plug
WO2005070333A1 (en) * 2004-01-13 2005-08-04 Orthobiologica, Inc. Drug delivery to a joint

Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8877193B2 (en) 2003-05-13 2014-11-04 DePuy Synthes Products, LLC. Transdiscal administration of anti-TNFα antibodies and growth differentiation factors
USRE49219E1 (en) 2003-11-26 2022-09-27 DePuy Synthes Products, Inc. Local intraosseous administration of bone forming agents and anti-resorptive agents, and devices therefor
EP2363122A1 (en) * 2006-07-26 2011-09-07 Medtronic, Inc. Clonidine to treat pain locally
WO2008067234A3 (en) * 2006-11-28 2008-07-31 Warsaw Orthopedic Inc Use of anti-cytokine agents for treating carpal and tarsal tunnel syndrome
WO2008067234A2 (en) * 2006-11-28 2008-06-05 Warsaw Orthopedic, Inc Use of anti-cytokine agents for treating carpal and tarsal tunnel syndrome
EP2134409A1 (en) * 2007-03-09 2009-12-23 Anthem Orthopaedics, LLC Implantable medicament delivery device and delivery tool and method for use therewith
EP2134409A4 (en) * 2007-03-09 2013-07-17 Anthem Orthopaedics Llc Implantable medicament delivery device and delivery tool and method for use therewith
WO2008157057A2 (en) * 2007-06-19 2008-12-24 Warsaw Orthopedic, Inc. Locally administrated low doses of corticosteroids
WO2008157057A3 (en) * 2007-06-19 2010-01-28 Warsaw Orthopedic, Inc. Locally administrated low doses of corticosteroids
US7910123B2 (en) 2007-09-05 2011-03-22 Warsaw Orthopedic Methods of treating a trauma or disorder of the knee joint by local administration and sustained-delivery of a biological agent
WO2009033046A1 (en) * 2007-09-05 2009-03-12 Warsaw Orthopedic, Inc. Apparatus for delivering treatment to a joint
US8986696B2 (en) 2007-12-21 2015-03-24 Depuy Mitek, Inc. Trans-capsular administration of p38 map kinase inhibitors into orthopedic joints
US8557271B2 (en) 2008-07-16 2013-10-15 Warsaw Orthopedic, Inc. Drug depot implantable within a joint
US8202531B2 (en) 2008-07-23 2012-06-19 Warsaw Orthopedic, Inc. Drug depots having one or more anchoring members
WO2010053786A3 (en) * 2008-10-29 2010-09-16 Warsaw Orthopedic, Inc. Drug depot delivery device and methods
WO2010053786A2 (en) * 2008-10-29 2010-05-14 Warsaw Orthopedic, Inc. Drug depot delivery device and methods
EP2349398A2 (en) * 2008-10-30 2011-08-03 Warsaw Orthopedic, Inc. Drug depot with anchor
WO2010059378A3 (en) * 2008-10-30 2010-08-12 Warsaw Orthopedic, Inc. Drug depot with anchor
JP2012507366A (en) * 2008-10-30 2012-03-29 ウォーソー・オーソペディック・インコーポレーテッド Drug depot with anchor
EP2349398A4 (en) * 2008-10-30 2012-04-04 Warsaw Orthopedic Inc Drug depot with anchor
US9623222B2 (en) 2008-10-30 2017-04-18 Warsaw Orthopedic, Inc. Drug depot with anchor
WO2010051383A3 (en) * 2008-10-31 2010-08-26 Warsaw Orthopedic, Inc. A device and method for delivery of a drug depot
US8702677B2 (en) 2008-10-31 2014-04-22 Warsaw Orthopedic, Inc. Device and method for directional delivery of a drug depot
CN102387833A (en) * 2009-03-20 2012-03-21 因卡伯实验室有限责任公司 Solid drug delivery apparatus, formulations and methods of use
US10384048B2 (en) 2014-07-25 2019-08-20 Warsaw Orthopedic, Inc. Drug delivery device and methods having an occluding member
US10478603B2 (en) 2014-07-25 2019-11-19 Warsaw Orthopedic, Inc. Drug delivery device and methods having a retaining member
US11464958B2 (en) 2014-07-25 2022-10-11 Warsaw Orthopedic, Inc. Drug delivery methods having an occluding member
US11504513B2 (en) 2014-07-25 2022-11-22 Warsaw Orthopedic, Inc. Drug delivery device and methods having a retaining member
US11759614B2 (en) 2015-11-23 2023-09-19 Warsaw Orthopedic, Inc. Enhanced stylet for drug depot injector
US10549081B2 (en) 2016-06-23 2020-02-04 Warsaw Orthopedic, Inc. Drug delivery device and methods having a retaining member
US11413442B2 (en) 2016-06-23 2022-08-16 Warsaw Orthopedic, Inc. Drug delivery device and methods having a retaining member
US11478587B2 (en) 2016-11-08 2022-10-25 Warsaw Orthopedic, Inc. Drug depot delivery system and method

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US7727954B2 (en) 2010-06-01
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US8357388B2 (en) 2013-01-22

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